N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase

ABSTRACT

N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula: 
                         
are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R 1 , R 2 , R 3  and R 4  are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

This application is a divisional of U.S. Ser. No. 10/493,280, filed Apr.20, 2004 now U.S. Pat. No. 7,169,780, which is the National Stage ofInternational Application No. PCT/GB02/004743, filed on Oct. 21, 2002,which claims the benefit under 35 U.S.C. 119(e) of U.S. ProvisionalApplication No. 60/339,568 filed on Oct. 26, 2001 and 60/362,191 filedon Mar. 6, 2002.

FIELD OF THE INVENTION

The present invention is directed to N-substituted5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides andpharmaceutically acceptable salts thereof, their synthesis, and theiruse as inhibitors of the HIV integrase enzyme. The compounds andpharmaceutically acceptable salts thereof of the present invention areuseful for preventing or treating infection by HIV and for treating ordelaying the onset of AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV. A commonfeature of retrovirus replication is the insertion by virally-encodedintegrase of proviral DNA into the host cell genome, a required step inHIV replication in human T-lymphoid and monocytoid cells. Integration isbelieved to be mediated by integrase in three steps: assembly of astable nucleoprotein complex with viral DNA sequences; cleavage of twonucleotides from the 3′ termini of the linear proviral DNA; covalentjoining of the recessed 3′ OH termini of the proviral DNA at a staggeredcut made at the host target site. The fourth step in the process, repairsynthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh, H. et al.,EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986);Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes havebeen shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhbitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. The particular advantage ofthe present invention is highly specific inhibition of HIV integrase andHIV replication.

SUMMARY OF THE INVENTION

The present invention is directed to novel hydroxypyrimidinonecarboxamides. These compounds are useful in the inhibition of HIVintegrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS and/or ARC, either as compounds or their pharmaceuticallyacceptable salts or hydrates (when appropriate), or as pharmaceuticalcomposition ingredients, whether or not in combination with otherHIV/AIDS antivirals, anti-infectives, immunomodulators, antibiotics orvaccines. More particularly, the present invention includes a compoundof Formula (I):

wherein

-   R¹ is    -   (1) —H,    -   (2) —C₁₋₆ alkyl, which is optionally substituted with one or        more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1        to 4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —OH,        —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)), —C(═O)—C₀₋₆        alkyl-N(R^(a)R^(b)), N(R^(a))—C(═O)—C₀₋₆ alkyl-N(R^(b)R^(c)),        —SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),        —N(R^(a))—C(═O)R^(b),

or —N(R²)C(═O)C(═O)N(R^(a)R^(b)),

-   -   (3) —R^(k),    -   (4) —C₁₋₆ alkyl-R^(k), wherein:        -   (i) the alkyl is optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently halogen,            —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —N(R^(a)R^(b)),            —N(R^(a))CO₂R^(b), —N(R^(a))C(═O)—C₀₋₆ alkyl-N(R^(b)R^(c)),            or —N(R^(a))—C₂₋₆ alkyl-OH with the proviso that the —OH is            not attached to the carbon alpha to N(R^(a)); and        -   (ii) the alkyl is optionally mono-substituted with —R^(s),            —C₁₋₆ alkyl-R^(s), —N(R^(a))—C(═O)—C₀₋₆ alkyl-R^(s),            —N(R^(a))—C₀₋₆ alkyl-R^(s), —O—C₀₋₆ alkyl-R^(s), or            —N(R^(a))—C(═O)—C₀₋₆ alkyl-R^(s); wherein R^(s) is            -   (a) aryl which is optionally substituted with one or                more substituents (e.g., optionally from 1 to 5, or 1 to                4, or 1 to 3, or 1 or 2 substituents; or is optionally                mono-substituted) each of which is independently                halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-OR^(a), —C₁₋₆                haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,                methylenedioxy attached to two adjacent carbon atoms, or                aryl;            -   (b) a 4- to 8-membered saturated heterocyclic ring                containing from 1 to 4 heteroatoms independently                selected from N, O and S; wherein the saturated                heterocyclic ring is optionally substituted with one or                more substituents (e.g., optionally from 1 to 6, or 1 to                5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is                optionally mono-substituted) each of which is                independently halogen, —C₁₋₆ alkyl, —C₁₋₆ alkyl-OR^(a),                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,                —C(═O)R^(a), —CO₂R^(a), —C(═O)—C₀₋₆ alkyl-N(R^(a)R^(b)),                —SO₂R^(a), oxo, aryl, or —C₁₋₆ alkyl-aryl; or            -   (c) a 5- to 7-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S; wherein the heteroaromatic ring is optionally                substituted with one or more substituents (e.g.,                optionally 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2                substituents; or is optionally mono-substituted) each of                which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆                alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆                haloalkyl, oxo, or aryl;    -   (5) —C₀₋₆ alkyl-O—C₀₋₆ alkyl-R^(k),    -   (6) —C₀₋₆ alkyl-S(O)_(n)—C₀₋₆ alkyl-R^(k),    -   (7) —O—C₁₋₆ alkyl-OR^(k),    -   (8) —O—C₁₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),    -   (9) —O—C₁₋₆ alkyl-S(O)_(n)R^(k),    -   (10) —C₀₋₆ alkyl-N(R^(a))—R^(k),    -   (11) —C₀₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-R^(k),    -   (12) —C₀₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-OR^(k),    -   (13) —C₀₋₆ alkyl-C(═O)—R^(k),    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))—C₀₋₆ alkyl-R^(k),    -   (15) —C₀₋₆ alkyl-N(R^(a))C(═O)—C₀₋₆ alkyl-R^(k),    -   (16) —C₀₋₆ alkyl-N(R^(a))C(═O)—O—C₀₋₆ alkyl-R^(k), or    -   (17) —C₀₋₆ alkyl-N(R^(a))C(═O)C(═O)R^(k);

-   R² is —C₁₋₆ alkyl which is optionally substituted with one or more    substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or    1 to 3, or 1 or 2 substituents; or is optionally mono-substituted)    each of which is independently    -   (1) halogen,    -   (2) —OH,    -   (3) —CN,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ haloalkyl,    -   (6) —C(═O)R^(a),    -   (7) —CO₂R^(a),    -   (8) —SR^(a),    -   (9) —S(═O)R^(a),    -   (10) —N(R^(a)R^(b)),    -   (11) —C(═O)N(R^(a)R^(b)),    -   (12) —N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(b)R^(c)),    -   (13) —SO₂R^(a),    -   (14) —N(R^(a))SO₂R^(b),    -   (15) —SO₂N(R^(a)R^(b)),    -   (16) —N(R^(a))—C(R^(b))═O,    -   (17) —C₃₋₈ cycloalkyl,    -   (18) aryl, wherein the aryl is optionally substituted with one        or more substituents (e.g., optionally from 1 to 5, or 1 to 4,        or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C₀₋₆        alkyl-N(R^(a)R^(b)), or —C₁₋₆ alkyl substituted with a 5- or        6-membered saturated heterocyclic ring containing from 1 to 4        heteroatoms independently selected from N, O and S;        -   wherein the saturated heterocyclic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₆ alkyl, oxo, or a 5- or 6-membered            heteroaromatic ring containing from 1 to 4 heteroatoms            independently selected from N, O and S; or    -   (19) a 5- to 8-membered monocyclic heterocycle which is        saturated or unsaturated and contains from 1 to 4 heteroatoms        independently selected from N, O and S; wherein the heterocycle        is optionally substituted with one or more substituents (e.g.,        optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or        2 substituents; or is optionally mono-substituted) each of which        is independently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, phenyl, or        naphthyl;

-   R³ is —H or —C₁₋₆ alkyl;

-   R⁴ is    -   (1) H,    -   (2) C₁₋₆ alkyl which is optionally substituted with one or more        substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to        4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —OH,        O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a)R^(b)),        —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a), —SO₂R^(a), or        —N(R^(a))CO₂R^(b),    -   (3) C₁₋₆ alkyl which is optionally substituted with one or more        substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to        4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —OH,        or O—C₁₋₄ alkyl, and which is substituted with 1 or 2        substituents each of which is independently:        -   (i) C₃₋₈ cycloalkyl,        -   (ii) aryl,        -   (iii) a fused bicyclic carbocycle consisting of a benzene            ring fused to a C₅₋₇ cycloalkyl,        -   (iv) a 5- or 6-membered saturated heterocyclic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S,        -   (v) a 5- or 6-membered heteroaromatic ring containing from 1            to 4 heteroatoms independently selected from N, O and S, or        -   (vi) a 9- or 10-membered fused bicyclic heterocycle            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein at least one of the rings is            aromatic,    -   (4) C₂₋₅ alkynyl optionally substituted with aryl,    -   (5) C₃₋₈ cycloalkyl optionally substituted with aryl,    -   (6) aryl,    -   (7) a fused bicyclic carbocycle consisting of a benzene ring        fused to a C₅₋₇ cycloalkyl,    -   (8) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 4 heteroatoms independently selected from N, O and S,    -   (9) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, or    -   (10) a 9- or 10-membered fused bicyclic heterocycle containing        from 1 to 4 heteroatoms independently selected from N, O and S,        wherein at least one of the rings is aromatic;    -   wherein        -   each aryl in (3)(ii) or the aryl (4), (5) or (6) or each            fused carbocycle in (3)(iii) or the fused carbocycle in (7)            is optionally substituted with one or more substituents            (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or            2 substituents; or is optionally mono-substituted) each of            which is independently halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆            alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)), —C₁₋₆            alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),            —CO₂R^(a), —C₁₋₆ alkyl-CO₂R^(a), —OCO₂R^(a), —SR^(a),            —S(═O)R^(a), —SO₂R^(a), —N(R^(a))SO₂R^(b),            —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),            —C₁₋₆ alkyl-N(R^(a))CO₂R^(b), aryl, —C₁₋₆ alkyl-aryl,            —O-aryl, or —C₀₋₆ alkyl-het wherein het is a 5- or            6-membered heteroaromatic ring containing from 1 to 4            heteroatoms independently selected from N, O and S, and het            is optionally fused with a benzene ring, and is optionally            substituted with one or more substituents (e.g., optionally            from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents;            or is optionally mono-substituted) each of which is            independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,            —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a);        -   each saturated heterocyclic ring in (3)(iv) or the saturated            heterocyclic ring in (8) is optionally substituted with one            or more substituents (e.g., optionally from 1 to 6, or 1 to            5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is            optionally mono-substituted) each of which is independently            halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,            —O—C₁₋₆ haloalkyl, oxo, aryl, or a 5- or 6-membered            heteroaromatic ring containing from 1 to 4 heteroatoms            independently selected from N, O and S; and        -   each heteroaromatic ring in (3)(v) or the heteroaromatic            ring in (9) or each fused bicyclic heterocycle in (3)(vi) or            the fused bicyclic heterocycle in (10) is optionally            substituted with one or more substituents (e.g., optionally            from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2            substituents; or is optionally mono-substituted) each of            which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, aryl, or            —C₁₋₆ alkyl-aryl;

-   or alternatively R³ and R⁴ together with the N to which both are    attached form a C₃₋₇ azacycloalkyl which is optionally substituted    with one or more substituents (e.g., optionally from 1 to 6, or 1 to    5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally    mono-substituted) each of which is independently —C₁₋₆ alkyl or oxo;

-   each R^(a), R^(b), R^(c), and R^(d) is independently —H or —C₁₋₆    alkyl;

-   R^(k) is carbocycle or heterocycle, wherein the carbocycle or    heterocycle is optionally substituted with one or more substituents    (e.g., optionally from 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1    to 3, or 1 or 2 substituents; or is optionally mono-substituted)    each of which is independently    -   (1) halogen,    -   (2) —OH,    -   (3) —CN,    -   (4) —C₁₋₆ alkyl, which is optionally substituted with one or        more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1        to 4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —OH,        —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),        —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (5) —O—C₁₋₆ alkyl, which is optionally substituted with one or        more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1        to 4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently halogen, —OH,        —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),        —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (6) —NO₂,    -   (7) oxo,    -   (8) —C(═O)R^(a),    -   (9) —CO₂R^(a),    -   (10) —SR^(a),    -   (11) —S(═O)R^(a),    -   (12) —N(R^(a)R^(b)),    -   (13) —C(═O)N(R^(a)R^(b)),    -   (14) —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),    -   (15) —N(R^(a))C(═O)R^(b),    -   (16) —SO₂R^(a),    -   (17) —SO₂N(R^(a)R^(b)),    -   (18) —N(R^(a))SO₂R^(b),    -   (19) —R^(m),    -   (20) —C₁₋₆ alkyl-R^(m), wherein the alkyl is optionally        substituted with one or more substituents (e.g., optionally from        1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents;        or is optionally mono-substituted) each of which is        independently halogen, —OH, —CN, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,        —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),        —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b), —SO₂R^(a), —N(R^(a))SO₂R^(b),        —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (21) —C₀₋₆ alkyl-N(R^(a))—C₀₋₆ alkyl-R^(m),    -   (22) —C₀₋₆ alkyl-O—C₀₋₆ alkyl-R^(m),    -   (23) —C₀₋₆ alkyl-S—C₀₋₆ alkyl-R^(m),    -   (24) —C₀₋₆ alkyl-C(═O)—C₀₋₆ alkyl-R^(m),    -   (25) —C(═O)—O—C₀₋₆ alkyl-R^(m),    -   (26) —C(═O)N(R^(a))—C₀₋₆ alkyl-R^(m),    -   (27) —N(R^(a))C(═O)—R^(m),    -   (28) —N(R^(a))C(═O)—C₁₋₆ alkyl-R^(m), wherein the alkyl is        optionally substituted with one or more substituents (e.g.,        optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or        2 substituents; or is optionally mono-substituted) each of which        is independently halogen, —OH, —CN, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a),        —S(═O)R^(a), —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (29) —N(R^(a))—C(═O)—N(R^(b))—C₀₋₆ alkyl-R^(m),    -   (30) —N(R^(a))—C(═O)—O—C₀₋₆ alkyl-R^(m),    -   (31) —N(R^(a))—C(═O)—N(R^(b))—SO₂—C₀₋₆ alkyl-R^(m),    -   (32) —C(═O)—C(═O)—N(R^(a)R^(b)),    -   (33) —C(═O)—C₁₋₆ alkyl-SO₂R^(a), or    -   (34) —C(═O)—C(═O)R^(m);

-   carbocycle in R^(k) is (i) a C₃ to C₈ monocyclic, saturated or    unsaturated ring, (ii) a C₇ to C₁₂ bicyclic ring system, or (iii) a    C₁₁ to C₁₆ tricyclic ring system, wherein each ring in (ii) or (iii)    is independent of or fused to the other ring or rings and each ring    is saturated or unsaturated;

-   heterocycle in R^(k) is (i) a 4- to 8-membered, saturated or    unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring    system, or (iii) an 11 to 16-membered tricyclic ring system; wherein    each ring in (ii) or (iii) is independent of or fused to the other    ring or rings and each ring is saturated or unsaturated; the    monocyclic ring, bicyclic ring system, or tricyclic ring system    contains from 1 to 6 heteroatoms selected from N, O and S and a    balance of carbon atoms; and wherein any one or more of the nitrogen    and sulfur heteroatoms is optionally be oxidized, and any one or    more of the nitrogen heteroatoms is optionally quaternized;

-   each R^(m) is independently C₃₋₈ cycloalkyl; aryl; a 5- to    8-membered monocyclic heterocycle which is saturated or unsaturated    and contains from 1 to 4 heteroatoms independently selected from N,    O and S; or a 9- to 10-membered bicyclic heterocycle which is    saturated or unsaturated and contains from 1 to 4 heteroatoms    independently selected from N, O and S; wherein any one or more of    the nitrogen and sulfur heteroatoms in the heterocycle or bicyclic    heterocycle is optionally oxidized and any one or more of the    nitrogen heteroatoms is optionally quaternized; and wherein    -   the cycloalkyl or the aryl defined in R^(m) is optionally        substituted with one or more substituents (e.g., optionally from        1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is        optionally mono-substituted) each of which is independently        halogen, —C₁₋₆ alkyl optionally substituted with —O—C₁₋₄ alkyl,        —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,        —N(R^(a)R^(b)), aryl, or —C₁₋₆ alkyl-aryl; and    -   the monocyclic or bicyclic heterocycle defined in R^(m) is        optionally substituted with one or more substituents (e.g.,        optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or        2 substituents; or is optionally mono-substituted) each of which        is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, —O—C₁₋₆ haloalkyl, oxo, aryl, —C₁₋₆ alkyl-aryl,        —C(═O)-aryl, —CO₂-aryl, —CO₂—C₁₋₆ alkyl-aryl, a 5- or 6-membered        saturated heterocyclic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S, or a 5- or 6-membered        heteroaromatic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S; and

-   each n is independently an integer equal to zero, 1 or 2;    or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the N-substituted hydroxypyrimidinonecarboxamides of Formula (I) above. These compounds and pharmaceuticallyacceptable salts thereof are HIV integrase inhibitors.

An embodiment of the present invention is a compound of Formula (I)exactly as defined above, except that in the definition of R^(k), R^(k)is optionally substituted with one or more substituents each of which isindependently one of the substituents (1) to (18), and is optionallymono-substituted with one of the substituents (19) to (34).

Another embodiment of the present invention is a compound of Formula (I)as originally defined above, except that the definition of R² includes aproviso that none of the following optional substituents is attached tothe carbon atom in the —C₁₋₆ alkyl group that is attached to the ringnitrogen: halogen, —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —SR^(a),—S(═O)R^(a), or —N(R^(a))—C(R^(b))═O. Stated another way, none of thesesubstituents is attached to the carbon atom alpha to the ring nitrogen.

Another embodiment of the present invention is a compound of Formula (I)as originally defined above except that in the definition of R¹, R¹ isone of substitutents (1) to (16) and in the definition of R^(k), R^(k)is optionally substituted with one or more substituents (e.g.,optionally from 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1to 2 substituents, or is optionally monosubstituted) each of which isindependently one of substitutents (1) to (31).

Another embodiment of the present invention is a compound of Formula(I), wherein R¹ is:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl, which is optionally substituted with one or        more substituents each of which is independently halogen, —OH,        —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),        —C(═O)—(CH₂)₀₋₃—N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₃—N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), —N(R^(a))—C(═O)R^(b),

-   -    or —N(R²)C(═O)C(═O)N(R^(a)R^(b)),    -   (3) —R^(k),    -   (4) —(CH₂)₁₋₃—R^(k), wherein:        -   (i) the —(CH₂)₁₋₃— moiety is optionally substituted with one            or more substituents each of which is independently halogen,            —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —N(R^(a)R^(b)),            —N(R^(a))CO₂R^(b), —N(R^(a))C(═O)—(CH₂)₀₋₃—N(R^(b)R^(c)), or            —N(R^(a))—(CH₂)₂₋₃—OH with the proviso that the —OH is not            attached to the carbon alpha to N(R^(a)); and        -   (ii) the —(CH₂)₁₋₃— moiety is optionally mono-substituted            with —R^(s), —C₁₋₆ alkyl-R^(s),            —N(R^(a))—C(═O)—(CH₂)₀₋₃—R^(s), —N(R^(a))—(CH₂)₀₋₃—R^(s),            —O—(CH₂)₀₋₃—R^(s), or —N(R^(a))—C(═O)—(CH₂)₀₋₃—R^(s);            wherein R^(s) is            -   (a) aryl which is optionally substituted with one or                more substituents each of which is independently                halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-OR^(a), —C₁₋₆                haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,                methylenedioxy attached to two adjacent carbon atoms, or                aryl;            -   (b) a 4- to 8-membered saturated heterocyclic ring                containing from 1 to 4 heteroatoms independently                selected from N, O and S; wherein the saturated                heterocyclic ring is optionally substituted with one or                more substituents each of which is independently                halogen, —C₁₋₆ alkyl, —C₁₋₆ alkyl-OR^(a), —C₁₋₆                haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,                —C(═O)R^(a), —CO₂R^(a), —C(═O)—(CH₂)₀₋₃—N(R^(a)R^(b)),                —SO₂R^(a), oxo, aryl, or —(CH₂)₁₋₃-aryl; or            -   (c) a 5- to 7-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S; wherein the heteroaromatic ring is optionally                substituted with one or more substituents each of which                is independently halogen, —C₁₋₆ alkyl, —C₁₋₆                alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆                haloalkyl, oxo, or aryl;    -   (5) —(CH₂)₀₋₃—O—(CH₂)₀₋₃—R^(k),    -   (6) —(CH₂)₀₋₃—S(O)_(n)—(CH₂)₀₋₃—R^(k),    -   (7) —(CH₂)₁₋₃—OR^(k),    -   (8) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k),    -   (9) —O—(CH₂)₁₋₃—S(O)_(n)R^(k),    -   (10) —(CH₂)₀₋₃—N(R^(a))—R^(k),    -   (11) —(CH₂)₀₋₃—N(R^(a))—(CH₂)₁₋₃—R^(k),    -   (12) —(CH₂)₀₋₃—N(R^(a))—(CH₂)₁₋₃—OR^(k),    -   (13) —(CH₂)₀₋₃—C(═O)—R^(k),    -   (14) —(CH₂)₀₋₃—C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k),    -   (15) —(CH₂)₀₋₃—N(R^(a))C(═O)—(CH₂)₀₋₃—R^(k),    -   (16) —(CH₂)₀₋₃—N(R^(a))C(═O)—O—(CH₂)₀₋₃—R^(k),    -   (17) —C(CH₃)₂N(R^(a))C(═O)R^(b),    -   (18) —C(CH₃)₂N(R^(a))C(═O)R^(k), or    -   (19) —C(CH₃)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c));        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment, R¹ is one of groups (1) to (16).

Another embodiment of the present invention is a compound of Formula(I), wherein R¹ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl, which is optionally substituted with from 1 to        4 substituents each of which is independently halogen, —OH, —CN,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)), —C(═O)—C₀₋₄        alkyl-N(R^(a)R^(b)), N(R^(a))—C(═O)—C₀₋₄ alkyl-N(R^(b)R^(c)),        —SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),        —N(R^(a))—C(═O)R^(b),

-   -    —N(R²)C(═O)C(═O)N(R^(a)R^(b)),    -   (3) —R^(k),    -   (4) —C₁₋₄ alkyl-R^(k), wherein:        -   (i) the alkyl is optionally substituted with from 1 to 4            substituents each of which is independently halogen, —OH,            —CN, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —N(R^(a)R^(b)),            —N(R^(a))CO₂R^(b), —N(R^(a))C(═O)—C₀₋₄ alkyl-N(R^(b)R^(c)),            or —N(R^(a))—(CH₂)₂₋₄—OH; and        -   (ii) the alkyl is optionally mono-substituted with —R^(s),            —N(R^(a))—C(═O)—C₀₋₄ alkyl-R^(s), —N(R^(a))—C₀₋₄            alkyl-R^(s), —O—C₀₋₄ alkyl-R^(s), or —N(R^(a))—C(═O)—C₀₋₄            alkyl-R^(s); wherein R^(s) is            -   (a) aryl which is optionally substituted with from 1 to                3 substituents each of which is independently halogen,                —OH, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl,                —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, methylenedioxy                attached to two adjacent carbon atoms, or phenyl;            -   (b) a 5- or 6-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S; wherein the heteroaromatic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently halogen, —C₁₋₄ alkyl, —C₁₋₄                alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄                haloalkyl, oxo, or phenyl; or            -   (c) a 5- or 6-membered saturated heterocyclic ring                containing from 1 to 4 heteroatoms independently                selected from N, O and S; wherein the saturated                heterocyclic ring is optionally substituted with from 1                to 3 substituents each of which is independently                halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,                —C(═O)R^(a), —CO₂R^(a), —C(═O)—C₀₋₄ alkyl-N(R^(a)R^(b)),                —SO₂R^(a), oxo, or phenyl,    -   (5) —(CH₂)₀₋₃—C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k),    -   (6) —C(C₁₋₄ alkyl)₂N(R^(a))C(═O)R^(b),    -   (7) —C(C₁₋₄ alkyl)₂N(R^(a))C(═O)R^(k), or    -   (8) —C(C₁₋₄ alkyl)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c));        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment, R¹ is one of groups (1) to (5).

Another embodiment of the present invention is a compound of Formula(I), wherein R¹ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl, which is optionally substituted with from 1 to        3 substituents each of which is independently halogen, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —N(R^(a)R^(b)), or —C(═O)—(CH₂)₀₋₂—N(R^(a)R^(b)),    -   (3) —R^(k),    -   (4) —(CH₂)₁₋₄—R^(k), wherein:        -   (i) the —(CH₂)₁₋₄— moiety is optionally substituted with 1            or 2 substituents each of which is independently halogen,            —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —N(R^(a)R^(b));            and        -   (ii) the —(CH₂)₁₋₄— moiety is optionally mono-substituted            with —R^(s) or —N(R^(a))—(CH₂)₁₋₂—R^(s); wherein R^(s) is            -   (a) phenyl which is optionally substituted with from 1                to 3 substituents each of which is independently                halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl; or            -   (b) a 5- or 6-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S; wherein the heteroaromatic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently halogen, —C₁₋₄ alkyl, —C₁₋₄                alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄                haloalkyl; or            -   (c) a 5- or 6-membered saturated heterocyclic ring                containing from 1 to 4 heteroatoms independently                selected from N, O and S; wherein the saturated                heterocyclic ring is optionally substituted with from 1                to 3 substituents each of which is independently                halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,                —C(═O)R^(a), or —CO₂R^(a),    -   (5) —C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k),    -   (6) —C(CH₃)₂N(R^(a))C(═O)R^(b),    -   (7) —C(CH₃)₂N(R^(a))C(═O)R^(k),    -   (8) —C(CH₃)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c));        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment, R¹ is one of groups (1) to (5).

Another embodiment of the present invention is a compound of Formula(I), wherein

-   R^(k) is C₃₋₈ cycloalkyl; aryl selected from phenyl and naphthyl; a    bicyclic carbocycle selected from indanyl and tetrahydronaphthyl; a    5- or 6-membered saturated heterocyclic ring containing from 1 to 4    heteroatoms independently selected from N, O and S; a 5- or    6-membered heteroaromatic ring containing from 1 to 4 heteroatoms    independently selected from N, O and S; or a bicyclic heterocycle    which is a benzene ring fused to a 5- or 6-membered saturated or    unsaturated heterocyclic ring containing from 1 to 3 heteroatoms    independently selected from N, O and S;

wherein the cycloalkyl, aryl, bicyclic carbocycle, saturatedheterocyclic ring, heteroaromatic ring, or bicyclic heterocycle isoptionally substituted with from 1 to 4 substituents each of which isindependently

-   -   (1) halogen,    -   (2) —OH,    -   (3) —CN,    -   (4) —C₁₋₄ haloalkyl,    -   (5) —C₁₋₄ alkyl, which is optionally substituted with from 1 to        3 substituents each of which is independently —OH, —CN, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a),        —S(═O)R^(a), —N(R^(a)R^(b)), —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (6) —O—C₁₋₄ haloalkyl    -   (7) —O—C₁₋₄ alkyl, which is optionally substituted with from 1        to 3 substituents each of which is independently —OH, —CN,        —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),        —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),        —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (8) —NO₂,    -   (9) oxo,    -   (10) —C(═O)R^(a),    -   (11) —CO₂R^(a),    -   (12) —SR^(a),    -   (13) —S(═O)R^(a),    -   (14) —N(R^(a)R^(b)),    -   (15) —C(═O)N(R^(a)R^(b)),    -   (16) —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),    -   (17) —N(R^(a))C(═O)R^(b),    -   (18) —SO₂R^(a),    -   (18) —SO₂N(R^(a)R^(b)),    -   (19) —N(R^(a))SO₂R^(b),    -   (20) —R^(m),    -   (21) —C₁₋₄ alkyl-R^(m),    -   (22) —(CH₂)₀₋₂—N(R^(a))—(CH₂)₀₋₂—R^(m),    -   (23) —(CH₂)₀₋₂—O—(CH₂)₀₋₂—R^(m),    -   (24) —(CH₂)₀₋₂—S—(CH₂)₀₋₂—R^(m),    -   (25) —(CH₂)₀₋₂—C(═O)—(CH₂)₀₋₂—R^(m),    -   (26) —C(═O)—O—(CH₂)₀₋₂—R^(m),    -   (27) —C(═O)N(R^(a))—R^(m), or    -   (28) —C(═O)—C(═O)N(R^(a)R^(b));        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment, the cycloalkyl, aryl, bicycliccarbocycle, saturated heterocyclic ring, heteroaromatic ring, orbicyclic heterocycle is optionally substituted with from 1 to 4substituents each of which is independently selected from the groups (1)to (27).

In an aspect of this embodiment, R^(k) (i.e., the cycloalkyl, aryl,bicyclic carbocycle, saturated heterocyclic ring, heteroaromatic ring,or bicyclic heterocycle) is optionally substituted with from 1 to 4substituents each of which is independently one of the substituents (1)to (19), and is optionally mono-substituted with one of the substituents(20) to (28). In a feature of this aspect, R^(k) is optionallysubstituted with from 1 to 4 substituents each of which is independentlyone of the substituents (1) to (19), and is mono-substituted with one ofthe substituents (20) to (28).

In another aspect of this embodiment, each R^(m) is independently C₃₋₇cycloalkyl; aryl selected from phenyl and naphthyl; a 5- or 6-memberedsaturated heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S; a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein any N is optionally oxidized to forman N-oxide; or a bicyclic heterocycle which is a benzene ring fused to a5- or 6-membered, saturated or unsaturated heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S; wherein

-   -   the cycloalkyl or the aryl defined in R^(m) is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —N(R^(a)R^(b)), phenyl, or        —(CH₂)₁₋₂-phenyl;    -   the saturated heterocyclic ring defined in R^(m) is optionally        substituted with from 1 to 4 substituents each of which is        independently —C₁₋₄ alkyl optionally substituted with —O—C₁₋₄        alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo,        phenyl, —(CH₂)₁₋₂-phenyl, —C(═O)-phenyl, —CO₂-phenyl,        —CO₂—(CH₂)₁₋₂-phenyl, a 5- or 6-membered saturated heterocyclic        ring containing from 1 to 4 heteroatoms independently selected        from N, O and S, or a 5- or 6-membered heteroaromatic ring        containing from 1 to 4 heteroatoms independently selected from        N, O and S; and    -   the heteroaromatic ring or the bicyclic heterocycle defined in        R^(m) is optionally substituted with from 1 to 4 substituents        each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo, phenyl, or        —(CH₂)₁₋₂-phenyl.

Another embodiment of the present invention is a compound of Formula(I), wherein R^(k) is phenyl; a 5- or 6-membered saturated heterocyclicring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1O atoms, and 0 or 1 S atoms; a 5- or 6-membered heteroaromatic ringcontaining 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1 Oatoms, and 0 or 1 S atoms; or a bicyclic heterocycle which is a benzenering fused to a 5- or 6-membered saturated heterocyclic ring containing1 or 2 nitrogen atoms;

and all other variables are as originally defined;

or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment,

-   -   (a) the phenyl, the saturated heterocyclic ring, heteroaromatic        ring, or bicyclic heterocycle is optionally substituted with        from 1 to 3 substituents each of which is independently        -   (1) fluoro,        -   (2) chloro,        -   (3) bromo,        -   (4) —OH        -   (5) —CF₃,        -   (6) —C₁₋₄ alkyl, which is optionally substituted with 1 or 2            substituents each of which is independently —OH, —CN,            —O—C₁₋₄ alkyl, —OCF₃, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)),            or N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)),        -   (7) —OCF₃,        -   (8) —O—C₁₋₄ alkyl        -   (9) —C(═O)R^(a),        -   (10) —CO₂R^(a),        -   (11) —SR^(a),        -   (12) —SR^(a),        -   (13) —N(R^(a)R^(b)),        -   (14) —C(═O)N(R^(a)R^(b)),        -   (15) —C(═O)—(CH₂)₁₋₂—N(R^(a)R^(b)),        -   (16) —N(R^(a))C(═O)R^(b), or        -   (17) —SO₂R^(a);    -   (b) the phenyl is optionally mono-substituted with        -   (1) —(CH₂)₁₋₂—R^(m), or        -   (2) —(CH₂)₀₋₂—N(R^(a))—(CH₂)₀₋₂—R^(m); and    -   (c) the saturated heterocyclic ring, heteroaromatic ring, or        bicyclic heterocycle is optionally mono- or di-substituted with        -   (1) oxo        -   (2) —(CH₂)₁₋₂—R^(m),        -   (3) —O—(CH₂)₁₋₂—R^(m), or        -   (4) —(CH₂)₀₋₁—C(═O)—(CH₂)₀₋₂—R^(m).

In a feature of the preceding aspect, each R^(m) is independentlycyclopropyl; phenyl; a 5- or 6-membered saturated heterocyclic ringselected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, and morpholinyl; or a 5- or 6-membered heteroaromatic ringselected from thienyl, pyridyl optionally in the form of an N-oxide,imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isooxazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl,triazolyl, tetrazolyl, furanyl, and pyridazinyl; wherein

-   -   the cyclopropyl is unsubstituted;    -   the phenyl is optionally substituted with from 1 to 3        substituents each of which is independently halogen, —C₁₋₄        alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, or —N(R^(a)R^(b));    -   the saturated heterocyclic ring is optionally substituted with 1        or 2 substituents each of which is independently —C₁₋₄ alkyl,        —CF₃, —O—C₁₋₄ alkyl, —OCF₃, oxo, phenyl, —(CH₂)₁₋₂-phenyl,        —C(═O)-phenyl, —CO₂-phenyl, or —CO₂—CH₂-phenyl; and    -   the heteroaromatic ring is optionally substituted with 1 or 2        substituents each of which is independently —C₁₋₄ alkyl, —CF₃,        —O—C₁₋₄ alkyl, —OCF₃, oxo, phenyl, or —(CH₂)₁₋₂-phenyl.

Another embodiment of the present invention is a compound of Formula(I), wherein R² is:

-   -   (1) —C₁₋₆ alkyl,    -   (2) —C₁₋₆ alkyl substituted with —N(R^(a)R^(b)),    -   (3) —C₁₋₆ alkyl substituted with phenyl, wherein the phenyl is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —C₀₋₄            alkyl-N(R^(a)R^(b)); and        -   (b) optionally mono-substituted with —C₁₋₄ alkyl substituted            with a 5- or 6-membered saturated heterocyclic ring            containing from 1 to 3 heteroatoms selected from 1 or 2 N            atoms, 0 or 1 O atoms, and 0 or 1 S atoms;            -   wherein the heterocyclic ring is optionally substituted                with from 1 to 3 substituents each of which is                independently —C₁₋₆ alkyl, oxo, or a 5- or 6-membered                heteroaromatic ring containing from 1 to 3 heteroatoms                selected from 1 to 3 N atoms, 0 or 1 O atom, and 0 or 1                S atom; or    -   (4) —C₁₋₆ alkyl optionally substituted with —OH and substituted        with a 5- or 6-membered saturated monocyclic heterocycle which        contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0        or 1 O atoms, and 0 or 1 S atoms; wherein the heterocycle is        optionally substituted with from 1 to 4 substituents each of        which is independently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, or        phenyl; or    -   (5) —C₁₋₆ alkyl substituted with a 5- or 6-membered        heteroaromatic ring which contains from 1 to 3 heteroatoms        selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S        atoms; wherein the heteroaromatic ring is optionally substituted        with from 1 to 4 substituents each of which is independently        —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, or phenyl;        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound of Formula (I)exactly as defined in the immediately preceding embodiment, except thatwhen R² is —C₁₋₆ alkyl substituted with —N(R^(a)R^(b)), it is with theproviso that —N(R^(a)R^(b)) is not attached to the carbon atom in the—C₁₋₆ alkyl group that is attached to the ring nitrogen (i.e., that the—N(R^(a)R^(b)) group is not attached to the carbon atom alpha to thering nitrogen).

Another embodiment of the present invention is a compound of Formula(I), wherein R² is methyl;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound of Formula(I), wherein R³ is —H or —C₁₋₄ alkyl;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

In an aspect of this embodiment, R³ is —H or methyl. In another aspectof this embodiment, R³ is —H.

Another embodiment of the present invention is a compound of Formula(I), wherein R⁴ is C₁₋₄ alkyl substituted with an aryl, which isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, —OH, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C₁₋₄ alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),—C₁₋₄ alkyl-CO₂R^(a), —OCO₂R^(a), —SR^(a), —S(═O)R^(a), —SO₂R^(a),—N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), —C₁₋₄ alkyl-N(R^(a))CO₂R^(b), methylenedioxy attachedto two adjacent ring carbon atoms, phenyl, —C₁₋₄ alkyl-phenyl,—O-phenyl, or —(CH₂)₀₋₂-het;

wherein het is a 5- or 6-membered heteroaromatic ring containing from 1to 4 heteroatoms independently selected from N, O and S, and het isoptionally fused with a benzene ring, and is optionally substituted with1 or 2 substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —CO₂R^(a);

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound of Formula(I), wherein R⁴ is —CH₂-phenyl, wherein the phenyl is optionallysubstituted with from 1 to 3 substituents each of which is independentlyfluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),—(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, —SR^(a),—N(R^(a)R^(b)) or phenyl;

each R^(a) and R^(b) is independently is H or —C₁₋₄ alkyl;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

In an aspect of the preceding embodiment, R⁴ is —CH₂-phenyl, wherein thephenyl is optionally substituted with from 1 to 3 substituents, each ofwhich is independently —F, —Br, —Cl, —OH, —C₁₋₄ alkyl, —C₁₋₄fluoroalkyl, —O—C₁₋₄ alkyl, —SO₂—C₁₋₄ alkyl, —S—C₁₋₄ alkyl, —N(CH₃)₂ or—O—C₁₋₄ fluoroalkyl. In another aspect of the preceding embodiment, R⁴is p-fluorobenzyl or 2,3-dimethoxybenzyl.

In another aspect of the preceding embodiment, the phenyl is optionallysubstituted with from 1 to 3 substituents each of which is independentlyfluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),—(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, or phenyl.

In an aspect of the preceding embodiment, the phenyl is optionallysubstituted with from 1 to 3 substituents, each of which isindependently —F, —Br, —Cl, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄alkyl, or —O—C₁₋₄ fluoroalkyl. In another aspect of the precedingembodiment, R⁴ is p-fluorobenzyl or 2,3-dimethoxybenzyl.

A class of compounds of the present invention includes any compound ofFormula (I), wherein

-   R¹ is —R^(k);-   R^(k) is phenyl which is

(a) optionally substituted with from 1 to 3 substituents each of whichis independently:

-   -   (1) halogen,    -   (2) —C₁₋₆ alkyl, which is optionally substituted with 1 or 2        substituents each of which is independently —O—C₁₋₆ alkyl,        —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),        —N(R^(a)R^(b)), —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (3) —C₁₋₆ haloalkyl,    -   (4) —O—C₁₋₆ haloalkyl,    -   (5) —C(═O)R^(a),    -   (6) —CO₂R^(a),    -   (7) —C(═O)N(R^(a)R^(b)), or    -   (8) —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)); and

(b) optionally mono-substituted with

-   -   (1) —C₁₋₄ alkyl-R^(m), or    -   (2) —C₀₋₄ alkyl-N(R^(a))—C₀₋₄ alkyl-R^(m);        wherein R^(m) is aryl selected from phenyl and naphthyl; a 5- or        6-membered saturated heterocyclic ring containing from 1 to 3        heteroatoms independently selected from N, O and S; or a 5- or        6-membered heteroaromatic ring containing from 1 to 3        heteroatoms independently selected from N, O and S; wherein    -   the aryl defined in R^(m) is optionally substituted with from 1        to 3 substituents each of which is independently halogen, —C₁₋₄        alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, or —N(R^(a)R^(b));    -   the saturated heterocyclic ring defined in R^(m) is optionally        substituted with from 1 to 3 substituents each of which is        independently —C₁₋₄ alkyl or oxo, and is additionally optionally        mono-substituted with phenyl, —(CH₂)₁₋₂-phenyl, —C(═O)-phenyl,        —CO₂-phenyl, —CO₂—(CH₂)₁₋₂-phenyl, or a 5- or 6-membered        heteroaromatic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S; and    -   the heteroaromatic ring defined in R^(m) is optionally        substituted with 1 or 2 substituents each of which is        independently —C₁₋₄ alkyl or oxo;        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present inventionincludes any compounds of Formula (I), wherein

-   R² is methyl;-   R³ is —H;-   R⁴ is:    -   (1) —CH₂-phenyl, wherein the phenyl is optionally substituted        with from 1 to 3 substituents each of which is independently        fluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl,        —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)),        —SO₂R^(a), —(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂,        —SR^(a), —N(R^(a)R^(b)) or phenyl; or    -   (2) a fused bicyclic carbocycle selected from

-   -    wherein Z¹ is —H or —OH; and        each R^(a) and R^(b) is independently is H or —C₁₋₄ alkyl;        and all other variables are as defined in the class;        or a pharmaceutically acceptable salt thereof.

Another sub-class of the preceding class of compounds of the presentinvention includes any compounds of Formula (I), wherein R⁴ is4-fluorobenzyl or 2,3-dimethoxybenzyl;

and all other variables are as defined in the class;

or a pharmaceutically acceptable salt thereof.

Still another sub-class of the preceding class of compounds of thepresent invention includes any compounds of Formula (I), wherein R² ismethyl; R³ is —H; R⁴ is 4-fluorobenzyl or 2,3-dimethoxybenzyl; eachR^(a) and R^(b) is independently is H or —C₁₋₄ alkyl; and all othervariables are as defined in the class; or a pharmaceutically acceptablesalt thereof.

Another class of the present invention includes any compound of Formula(II):

wherein

-   Q is:    -   (1) methyl which is optionally substituted with 1 or 2 of        —O—C₁₋₄ alkyl,    -   (2) phenyl which is optionally substituted with from 1 to 3        substituents each of which is independently —F, —Cl, Br, —C₁₋₄        alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, methylenedioxy attached to        two adjacent carbon atoms, or phenyl, or    -   (3) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 3 heteroatoms independently selected from N, O and S;        wherein the saturated heterocyclic ring is optionally        substituted with 1 or 2 substituents each of which is        independently —F, —Cl, —Br, —C₁₋₄ alkyl, oxo, phenyl, or        —C(═O)-phenyl;-   T is:    -   (1) —H,    -   (2) —OH,    -   (3) methyl or ethyl, optionally substituted with —OH or —O—C₁₋₄        alkyl,    -   (4) —O—C₁₋₄ alkyl    -   (5) —N(R^(a)R^(b)),    -   (6) —N(R^(a))—(CH₂)₂—OH,    -   (7) —N(R^(a))—CO₂R^(b),    -   (8) —N(R^(a))—C(═O)—(CH₂)₁₋₂—N(R^(a)R^(b)),    -   (9) —R^(s),    -   (10) —(CH₂)₁₋₂—R^(s), or    -   (11) —(CH₂)₀₋₂—N(R^(a))—(CH₂)₀₋₃—R^(s);-   R^(s) is:    -   (1) phenyl optionally substituted with from 1 to 4 substituents        each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄        alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,        or —N(R^(a)R^(b));    -   (2) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 3 heteroatoms independently selected from N, O and S;        which is optionally substituted with from 1 to 4 substituents        each of which is independently —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a),        —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a),        oxo, phenyl, or —CH₂-phenyl; or    -   (3) a 5- or 6-membered heteroaromatic ring containing from 1 to        3 heteroatoms independently selected from N, O and S; which is        optionally substituted with from 1 to 4 substituents each of        which is independently —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄        haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo;-   R² is    -   (1) —C₁₋₄ alkyl,    -   (2) —C₁₋₄ alkyl substituted with —N(R^(a)R^(b)), or    -   (3) —C₁₋₄ alkyl substituted with a 5- or 6-membered saturated        monocyclic heterocycle which contains from 1 to 3 heteroatoms        selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S        atoms; wherein the saturated heterocycle is optionally        substituted with from 1 to 4 substituents each of which is        independently a —C₁₋₄ alkyl;-   R³ is —H or —C₁₋₄ alkyl;-   R⁴ is —CH₂-phenyl, wherein the phenyl is optionally substituted with    from 1 to 3 substituents each of which is independently fluoro,    bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl,    —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),    —(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, —SR^(a),    —N(R^(a)R^(b)) or phenyl;-   each R^(a) and R^(b) is independently is H or —C₁₋₄ alkyl; and-   s is an integer equal to zero, 1, or 2;    or a pharmaceutically acceptable salt thereof.

In an aspect of this class, R⁴ is —CH₂-phenyl, wherein the phenyl isoptionally substituted with from 1 to 3 substituents each of which isindependently fluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl,—(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a), —(CH₂)₀₋₂—CO₂R^(a),—(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, or phenyl

A sub-class of the preceding class of compounds of the present inventionincludes any compounds of Formula (II) exactly as defined in thepreceding class, except that when R² is —C₁₋₄ alkyl substituted with—N(R^(a)R^(b)), it is with the proviso that —N(R^(a)R^(b)) is notattached to the carbon atom in the —C₁₋₄ alkyl group that is attached tothe ring nitrogen (i.e., that the —N(R^(a)R^(b)) group is not attachedto the carbon atom alpha to the ring nitrogen).

Another sub-class of the preceding class of compounds of the presentinvention includes any compounds of Formula (II), wherein

-   Q is phenyl;-   T is:    -   (1) —H,    -   (2) —N(R^(a)R^(b)),    -   (3) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 3 heteroatoms independently selected from N, O and S;        which is optionally substituted with 1 or 2 substituents each of        which is independently —C₁₋₄ alkyl or —C(═O)R^(a), or    -   (4) —N(R^(a))—(CH₂)₁₋₂-heteroaromatic, wherein the        heteroaromatic is a 5- or 6-membered ring containing 1 or 2 N        atoms;-   R² is methyl;-   R³ is —H; and-   R⁴ is —CH₂-phenyl, wherein the phenyl is optionally substituted with    1 or 2 substituents each of which is independently —F, —Cl, —Br,    —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —SO₂CH₃, —SCH₃, —N(CH₃)₂ or —OCF₃;-   each R^(a) and R^(b) is independently —H, methyl or ethyl; and-   s is an integer equal to zero or 1;    or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is —CH₂-phenyl, wherein the phenyl isoptionally substituted with 1 or 2 substituents each of which isindependently —F, —Cl, —Br, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃.

Another class of compounds of the present invention includes anycompound of Formula (I), wherein

-   R¹ is —R^(k);-   R^(k) is (i) a 5- or 6-membered saturated heterocyclic ring    containing from 0 to 1 oxygen atoms and from 1 to 3 nitrogen atoms    or (ii) a bicyclic heterocycle which is a benzene ring fused to a 5-    or 6-membered saturated heterocyclic ring containing from 0 to 1    oxygen atoms and from 1 to 3 nitrogen atoms;

wherein the saturated heterocyclic ring or bicyclic heterocycle isoptionally substituted with from 1 to 3 substituents each of which isindependently

-   -   (1) —C₁₋₄ alkyl, which is optionally substituted with from 1 to        4 substituents each of which is independently halogen, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a),        —S(═O)R^(a), —N(R^(a)R^(b)), —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),        N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (2) —OH,    -   (3) —C(═O)R^(a),    -   (4) —CO₂R^(a),    -   (5) —C(═O)N(R^(a)R^(b)),    -   (6) —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),    -   (7) —SR^(a),    -   (8) —S(═O)R^(a),    -   (9) —SO₂R^(a),    -   (10) —N(R^(a)R^(b)),    -   (11) —R^(m),    -   (12) —C₁₋₄ alkyl-R^(m), wherein the alkyl is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, —OH, —CN, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,        —O—C₁₋₄ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),        —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b), —SO₂R^(a), —N(R^(a))SO₂R^(b),        —SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O,    -   (13) —C₀₋₄ alkyl-N(R^(a))—C₀₋₄ alkyl-R^(m),    -   (14) —C₀₋₄ alkyl-O—C₀₋₄ alkyl-R^(m),    -   (15) —C₀₋₄ alkyl-S—C₀₋₄ alkyl-R^(m),    -   (16) —C₀₋₄ alkyl-C(═O)—C₀₋₄ alkyl-R^(m),    -   (17) —C(═O)—O—C₀₋₄ alkyl-R^(m), or    -   (18) —C(═O)N(R^(a))—C₀₋₄ alkyl-R^(m);        wherein each R^(m) is independently —C₃₋₆ cycloalkyl; aryl        selected from phenyl and naphthyl; a 5- or 6-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S; or a 5- or 6-membered        heteroaromatic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein any N is        optionally oxidized to form an N-oxide; wherein    -   the aryl is optionally substituted with from 1 to 3 substituents        each of which is independently halogen, —C₁₋₄ alkyl, —CF₃,        —O—C₁₋₄ alkyl, —OCF₃, or —N(R^(a)R^(b));    -   the saturated heterocyclic ring is optionally substituted with        from 1 to 3 substituents each of which is independently —C₁₋₄        alkyl or oxo, and is additionally optionally mono-substituted        with phenyl, —(CH₂)₁₋₂-phenyl, —C(═O)-phenyl, —CO₂-phenyl, or        —CO₂—(CH₂)₁₋₂-phenyl; and    -   the heteroaromatic ring is optionally substituted with 1 or 2        substituents each of which is independently halogen, —C₁₋₄        alkyl, or oxo;        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present inventionincludes any compounds of Formula (I), wherein

-   R¹ is:

-   R⁸ is:    -   (1) —H,    -   (2) —C₁₋₄ alkyl, which is optionally substituted with 1 or 2        substituents each of which is independently —OH, —O—C₁₋₄ alkyl,        —OCF₃, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —N(R^(a)R^(b)), or        —C(═O)N(R^(a)R^(b)),    -   (3) —C(═O)R^(a),    -   (4) —CO₂R^(a),    -   (5) —C(═O)N(R^(a)R^(b)),    -   (6) —C(═O)—(CH₂)₁₋₂—N(R^(a)R^(b)),    -   (7) —SO₂R^(a),    -   (8) —(CH₂)₁₋₂—R^(m),    -   (9) —(CH₂)₀₋₂—C(═O)—(CH₂)₀₋₂—R^(m),    -   (10) —C(═O)—O—(CH₂)₀₋₂—R^(m), or    -   (11) —C(═O)N(R^(a))—(CH₂)₀₋₂—R^(m);-   R¹⁰ is —H, —OH, —C₁₋₄ alkyl, —O—C₁₋₄ alkyl, —N(R^(a)R^(b)), or    —O—(CH₂)₁₋₂—R^(m);-   R¹² is    -   (1) —H,    -   (2) —C₁₋₄ alkyl, which is optionally substituted with 1 or 2        substituents each of which is independently —OH, —O—C₁₋₄ alkyl,        —OCF₃, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —N(R^(a)R^(b)), or        —C(═O)N(R^(a)R^(b)),    -   (3) —C(═O)R^(a),    -   (4) —CO₂R^(a),    -   (5) —C(═O)—(CH₂)₁₋₂—N(R^(a)R^(b)), or    -   (6) —SO₂R^(a);-   R² is methyl;-   R³ is —H or methyl;-   R⁴ is —CH₂-phenyl, wherein the phenyl is optionally substituted with    from 1 to 3 substituents each of which is independently fluoro,    bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl,    —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),    —(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, —SR^(a),    —N(R^(a)R^(b)) or phenyl; and-   each R^(a) and R^(b) is independently —H or —C₁₋₄ alkyl;    or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is —CH₂-phenyl, wherein the phenyl isoptionally substituted with from 1 to 3 substituents each of which isindependently fluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl,—(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a), —(CH₂)₀₋₂—CO₂R^(a),—(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, or phenyl.

Another class of the present invention includes any compound of Formula(III):

wherein R² is:

-   -   (1) —C₁₋₆ alkyl,    -   (2) —C₁₋₆ alkyl substituted with —N(R^(a)R^(b)),    -   (3) —C₁₋₆ alkyl substituted with phenyl which is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —C₀₋₆            alkyl-N(R^(a)R^(b)); and        -   (b) optionally mono-substituted with —C₁₋₄ alkyl substituted            with a 5- or 6-membered saturated heterocyclic ring            containing from 1 to 3 heteroatoms selected from 1 or 2 N            atoms, 0 or 1 O atoms, and 0 or 1 S atoms;        -   wherein the heterocyclic ring is optionally substituted with            from 1 to 3 substituents each of which is independently            —C₁₋₆ alkyl, oxo, or a 5- or 6-membered heteroaromatic ring            containing from 1 to 3 heteroatoms selected from 1 to 3 N            atoms, 0 or 1 O atom, and 0 or 1 S atom;    -   (4) —C₁₋₆ alkyl optionally substituted with —OH and substituted        with a 5- or 6-membered saturated monocyclic heterocycle which        contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0        or 1 O atoms, and 0 or 1 S atoms; wherein the heterocycle is        optionally substituted with from 1 to 4 substituents each of        which is independently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, or        phenyl; or    -   (5) —C₁₋₆ alkyl substituted with a 5- or 6-membered        heteroaromatic ring which contains from 1 to 3 heteroatoms        selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S        atoms; wherein the heteroaromatic ring is optionally substituted        with from 1 to 4 substituents each of which is independently        —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, or phenyl;        and all other variables are as originally defined above;        or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present inventionincludes any compounds of Formula (III) exactly as defined in thepreceding class, except that when R² is —C₁₋₆ alkyl substituted with—N(R^(a)R^(b)), it is with the proviso that —N(R^(a)R^(b)) is notattached to the carbon atom in the —C₁₋₆ alkyl group that is attached tothe ring nitrogen (i.e., that the —N(R^(a)R^(b)) group is not attachedto the carbon atom alpha to the ring nitrogen).

Another sub-class of the preceding class of compounds of the presentinvention includes any compounds of Formula (III), wherein

-   R² is:    -   (1) —C₁₋₄ alkyl,    -   (2) —(CH₂)₁₋₃—N(R^(a)R^(b)),    -   (3) —(CH₂)₁₋₃-phenyl, wherein the phenyl is:        -   (a) optionally substituted with from 1 to 3 substituents            each of which is independently fluoro, chloro, bromo, —C₁₋₄            alkyl, —CF₃, —O—C₁₋₄ alkyl, —O—CF₃, or            —(CH₂)₁₋₃—N(R^(a)R^(b)); and        -   (b) optionally mono-substituted with —(CH₂)₁₋₃-saturated            heterocycle which is a 5- or 6-membered saturated            heterocyclic ring containing from 1 to 3 heteroatoms            selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S            atoms, wherein the heterocyclic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl or pyridyl;    -   (4) —(CH₂)₁₋₃-saturated heterocycle, wherein the —(CH₂)₁₋₃—        moiety is optionally substituted with an —OH and the saturated        heterocycle is a 5- or 6-membered saturated monocyclic        heterocycle which contains from 1 to 3 heteroatoms selected from        1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; wherein the        heterocycle is optionally substituted with from 1 to 3        substituents each of which is independently a —C₁₋₄ alkyl; or    -   (5) —(CH₂)₁₋₃-pyridyl;-   R³ is —H or methyl;-   R⁴ is —CH₂-phenyl, wherein the phenyl is optionally substituted with    from 1 to 3 substituents each of which is independently fluoro,    bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl,    —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),    —(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, —SR^(a),    —N(R^(a)R^(b)) or phenyl; and-   each R^(a) and R^(b) is independently is H or —C₁₋₄ alkyl;    or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is —CH₂-phenyl, wherein the phenyl isoptionally substituted with from 1 to 3 substituents each of which isindependently fluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl,—(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a), —(CH₂)₀₋₂—CO₂R^(a),—(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, or phenyl.

Another class of compounds of the present invention includes anycompound of Formula (I), wherein

-   R¹ is —C(═O)NH—(CH₂)₁₋₂—R^(k); and-   R^(k) is (i) a 5- or 6-membered saturated heterocyclic ring    containing from 1 to 3 heteroatoms independently selected from N, O    and S, or (ii) a 5- or 6-membered heteroaromatic ring containing    from 1 to 3 heteroatoms independently selected from N, O and S;    and all other variables are as originally defined above;    or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present inventionincludes any compounds of Formula (I), wherein

-   R¹ is —C(═O)NH—(CH₂)₁₋₂—R^(k); and-   R^(k) is (i) a 5- or 6-membered saturated heterocyclic ring    containing from 1 to 3 heteroatoms independently selected from N, O    and S, or (ii) a 5- or 6-membered heteroaromatic ring containing    from 1 to 3 heteroatoms independently selected from N, O and S;-   R² is methyl;-   R³ is —H or methyl;-   R⁴ is —CH₂-phenyl, wherein the phenyl is optionally substituted with    from 1 to 3 substituents each of which is independently fluoro,    bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl,    —O—C₁₋₄ fluoroalkyl, —(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a),    —(CH₂)₀₋₂—CO₂R^(a), —(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, —SR^(a),    —N(R^(a)R^(b)) or phenyl; and-   each R^(a) and R^(b) is independently —H or —C₁₋₄ alkyl;    or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is —CH₂-phenyl, wherein the phenyl isoptionally substituted with from 1 to 3 substituents each of which isindependently fluoro, bromo, chloro, —OH, —C₁₋₄ alkyl, —C₁₋₄fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl,—(CH₂)₁₋₂—N(R^(a)R^(b)), —SO₂R^(a), —(CH₂)₀₋₂—CO₂R^(a),—(CH₂)₀₋₂—N(R^(a))CO₂R^(b), —NO₂, or phenyl.

It is to be understood that additional embodiments of the presentinvention include, but are not limited to, compounds of Formula Iwherein each of two or three or more of R¹, R², R³, R⁴, R^(a), R^(b),R^(c), R^(d), R^(k) and R^(m) is independently defined in accordancewith its definition in one of the embodiments or an aspect thereof asset forth above, or in accordance with its definition in one of theforegoing classes set forth above or a sub-class or feature thereof. Anyand all possible combinations of these variables in Formula I areadditional embodiments within the scope of the present invention.

An aspect of the present invention is a compound selected from the groupconsisting of

-   N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-2-{4-[(dimethylamino)methyl]phenyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-2-{4-[(dimethylamino)methyl]phenyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(piperidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{4-[(diethylamino)methyl]phenyl}-N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{4-[(diethylamino)methyl]phenyl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(dimethylamino)(phenyl)methyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-2-[(4-formylpiperazin-1-yl)(phenyl)methyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{phenyl[(pyridin-3-ylmethyl)amino]methyl}-1,6-dihydropyrimidine-4-carboxamide;-   2-benzyl-1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-2-(2-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-benzyl-N-(2,3-dimethoxybenzyl)-1-[2-(dimethylamino)ethyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{4-[(2-pyridin-3-ylpiperidin-1-yl)methyl]phenyl}-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-[4-fluoro-2-(trifluoromethyl)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(3-chloro-4-methylbenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   5-hydroxy-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1-methyl-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(4-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-2-(4-{[(4-fluorobenzyl)amino]methyl}phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyrimidine-4-carboxamide;-   2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-pyrrolidin-1-ylethyl)-1,6-dihydropyrimidine-4-carboxamide;-   2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-piperidin-1-ylethyl)-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzylpiperidin-3-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   1-{3-[(dimethylamino)methyl]benzyl)-N-(4-fluorobenzyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-1-[2-(dimethylamino)ethyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyrimidine-4-carboxamide;-   N4-(4-fluorobenzyl)-5-hydroxy-1-methyl-N2-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-[3-(pyrrolidin-1-ylmethyl)benzyl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-[3-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-{3-[(4-methylpiperazin-1-yl)methyl]benzyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{3-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-[2-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-pyrrolidin-2-yl-1,6-dihydropyrimidine-4-carboxamide;-   N4-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-N2-(pyridin-2-ylmethyl)-1,6-dihydropyrimidine-2,4-dicarboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-[4-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[2-(4-benzoylpiperazin-1-yl)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(N,N-dimethylglycyl)piperidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-2,3-dihydro-1H-indol-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(1,2,3,4-tetrahydroquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   tert-butyl    (2S,4R)-4-(benzyloxy)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate;-   tert-butyl    (2S,4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-hydroxypyrrolidine-1-carboxylate;-   2-[(2S,4R)-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-4-(benzyloxy)-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   tert-butyl    3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperazine-1-carboxylate;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   (+)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide-   (−)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide-   2-(1-ethyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzoylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)piperidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpyrrolidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-4-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(dimethylamino)-2-phenylethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(1-isobutyl-2,3-dihydro-1H-indol-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(1-isopropyl-2,3-dihydro-1H-indol-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(N,N-dimethylglycyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{1-[(6-bromopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperazin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzoyl-4-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(cyclopropylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-(methylsulfonyl)pyrrolidin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(4-methylmorpholin-3-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1,4-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-3-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-acetyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(1-isonicotinoylpyrrolidin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{1-[(ethylamino)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-methyl-1H-imidazol-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-acetyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(anilinocarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-oxidopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-[(4R)-3-acetyl-1,3-thiazolidin-4-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-methyl-4-(methylsulfonyl)piperazin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylthiomorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-[4-fluoro-2-(methylsulfonyl)benzyl]-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(3-acetyl-1,3-thiazolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(acetylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(4-acetyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-methyl-4-(pyrazin-2-ylcarbonyl)piperazin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-5-hydroxy-1-methyl-N-[2-(methylthio)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-{1-[(1H-imidazol-5-ylcarbonyl)amino]-1-methylethyl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-benzoyl-4-(pyrazin-2-ylcarbonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(4-benzoyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[4-(benzyloxy)-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-5-hydroxy-N-(2-methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide;-   2-(1-acetylpyrrolidin-2-yl)-N-[2-(dimethylamino)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-[4-hydroxy-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]imidazo[2,1-b][1,3]thiazole-6-carboxamide;-   2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-4-[(1-methyl-1H-imidazol-2-yl)carbonyl]piperazin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N1-{1-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-methylethyl}-N2,N2-dimethylethanediamide;-   2-(4-acetyl-1,2-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrimidin-4-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrimidin-5-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-[(1H-pyrazol-5-ylcarbonyl)amino]ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2R,4R)-1-acetyl-4-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{1-[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-{1-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-methylethyl}imidazo[2,1-b][1,3]thiazole-6-carboxamide;-   2-[(2R,4R)-1-benzoyl-4-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)-1-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1,2-dimethyl-4-(methylsulfonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(methylsulfonyl)acetyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-1-acetyl-4,4-difluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2R,4R)-1-acetyl-4-ethoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[morpholin-4-yl(oxo)acetyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2R,4R)-1-[(dimethylamino)(oxo)acetyl]-4-methoxypyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-4,4-difluoro-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{(2S,4S)-1-methyl-4-[(methylsulfonyl)amino]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{1-[(dimethylamino)sulfonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2R,4R)-4-ethoxy-1-[(methylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-4,4-difluoro-1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S)-4,4-difluoro-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2S)-1-[(dimethylamino)(oxo)acetyl]4,4-difluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[morpholin-4-yl(oxo)acetyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2S)-1-[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2S)-1-[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluoro-2-methoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N1,N2,N2-trimethylethanediamide;-   2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(4-fluoro-2-methoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-2-[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{(2S,4S)-1-[(dimethylamino)(oxo)acetyl]-4-fluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N1-[1-(4-{[(3-chloro-4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide;    and pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a compound selected from thegroup consisting of:

-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-oxidopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-4-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   (+)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide-   (−)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-1-acetyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-3-ylcarbonyl)pyrrolidin-2-yl]1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-2-(1-isonicotinoylpyrrolidin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1,4-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-methyl-1H-imidazol-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(1-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-(methylsulfonyl)pyrrolidin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(4R)-3-acetyl-1,3-thiazolidin-4-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-{1-[(ethylamino)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(2S,4R)-4-(benzyloxy)-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[1-(dimethylamino)-2-phenylethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   2-[(dimethylamino)(phenyl)methyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;-   N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide;    and pharmaceutically acceptable salts thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising a compound of Formula (I)and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) an effective amount of a compound of Formula(I) and a pharmaceutically acceptable carrier.

(c) The pharmaceutical composition of (a) or (b), further comprising atherapeutically effective amount of an HIV infection/ADS treatment agentselected from the group consisting of HIV/AIDS antiviral agents,immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (c), wherein the HIVinfection/AIDS treatment agent is an antiviral selected from the groupconsisting of HIV protease inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, and nucleoside HIV reverse transcriptaseinhibitors.

(e) A combination useful for inhibiting HIV integrase, for treating orpreventing infection by HIV, or for preventing, treating or delaying theonset of AIDS, which is a therapeutically effective amount of a compoundof Formula (I) and a therapeutically effective amount of an HIVinfection/AIDS treatment agent selected from the group consisting ofHIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.

(f) The combination of (e), wherein the HIV infection/AIDS treatmentagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors andnucleoside HIV reverse transcriptase inhibitors.

(g) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of a compound of Formula (I).

(h) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject atherapeutically effective amount of a compound of Formula (I).

(i) The method of (h), wherein the compound of Formula (I) isadministered in combination with a therapeutically effective amount ofat least one antiviral selected from the group consisting of HIVprotease inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, and nucleoside HIV reverse transcriptase inhibitors.

(j) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of a compound of Formula (I).

(k) The method of (j), wherein the compound is administered incombination with a therapeutically effective amount of at least oneantiviral selected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, and nucleoside HIVreverse transcriptase inhibitors

(l) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b), (c) or (d) or the combination of (e) or (f).

(m) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(n) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HIV protease, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreHIV/AIDS treatment agents selected from HIV/AIDS antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt.

As used herein, the term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means linear orbranched chain alkyl groups having from 1 to 6 carbon atoms and includesall of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-,sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl” meansn-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means adirect covalent bond. For example, when R¹ in Compound I is —C₀₋₆alkyl-O—C₀₋₆ alkyl-R^(k), then R¹ is —O—R^(k) when both alkyl groups areC₀ alkyl. Similarly, when an integer defining the presence of a certainnumber of atoms in a group is equal to zero, it means that the atomsadjacent thereto are connected directly by a bond. For example, thecompound of Formula (II) has

as a substituent at the 2-position of the pyrimidinone ring, wherein sis an integer equal to zero, 1 or 2. When s is zero, the substituent hasthe following structure:

The term “—C₁₋₆ alkyl-” refers to a C₁ to C₆ linear or branched alkylgroup as just defined which is bivalent. It can alternatively bereferred to as “C₁₋₆ alkylene” or “C₁₋₆ alkanediyl”. A class ofalkylenes of particular interest with respect to the invention is—(CH₂)₁₋₆—, and sub-classes of particular interest include —(CH₂)₁₋₄—,—(CH₂)₁₋₃—, —(CH₂)₁₋₂—, and —CH₂—.

The term “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) means linear or branchedchain alkynyl groups having from 2 to 5 carbon atoms and includes all ofthe pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl,1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms suchas “C₂₋₃ alkynyl” have an analogous meaning.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ringof an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). The terms “C₃₋₇ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₇cycloalkyl” and the like have analogous meanings.

The term “C₃₋₇ azacycloalkyl” (or “C₃-C₇ azacycloalkyl”) means asaturated cyclic ring consisting of one nitrogen and from three to sevencarbon atoms (i.e., azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl).

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “carbocycle” (and variations thereof such as “carbocyclic” or“carbocyclyl”) as used herein refers to (i) a C₃ to C₈ monocyclic,saturated or unsaturated ring, (ii) a C₇ to C₁₂ bicyclic ring system, or(iii) a C₁₁ to C₁₆ tricyclic ring system, wherein each ring in (ii) or(iii) is independent of or fused to the other ring or rings and eachring is saturated or unsaturated. The carbocycle may be attached to therest of the molecule at any carbon atom which results in a stablecompound. The fused bicyclic carbocycles are a subset of thecarbocycles; i.e., the term “fused bicyclic carbocycle” generally refersto a C₇ to C₁₀ bicyclic ring system in which each ring is saturated orunsaturated and two adjacent carbon atoms are shared by each of therings in the ring system. Fused tricyclic carbocycles have an analogousmeaning. A subset of the fused bicyclic carbocycles are those bicycliccarbocycles in which one ring is a benzene ring and the other ring issaturated or unsaturated, with attachment via any carbon atom thatresults in a stable compound. Representative examples of this subsetinclude the following:

The term “aryl” refers to aromatic mono- and poly-carbocyclic ringsystems, wherein the individual carbocyclic rings in the polyringsystems are fused or attached to each other via a single bond. Suitablearyl groups include phenyl, naphthyl, and biphenylenyl.

The term “heterocycle” (and variations thereof such as “heterocyclic” or“heterocyclyl”) broadly refers to (i) a 4- to 8-membered, saturated orunsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ringsystem, or (iii) an 11 to 16-membered tricyclic ring system; whereineach ring in (ii) or (iii) is independent of or fused to the other ringor rings and each ring is saturated or unsaturated, and the monocyclicring, bicyclic ring system, or tricyclic ring system contains one ormore heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4heteroatoms) selected from N, O and S and a balance of carbon atoms (themonocylic ring typically contains at least one carbon atom and the ringsystems typically contain at least two carbon atoms); and wherein anyone or more of the nitrogen and sulfur heteroatoms is optionally beoxidized, and any one or more of the nitrogen heteroatoms is optionallyquaternized. The heterocyclic ring may be attached at any heteroatom orcarbon atom, provided that attachment results in the creation of astable structure. When the heterocyclic ring has substituents, it isunderstood that the substituents may be attached to any atom in thering, whether a heteroatom or a carbon atom, provided that a stablechemical structure results.

Saturated heterocyclics form a subset of the heterocycles; i.e., theterm “saturated heterocyclic” generally refers to a heterocycle asdefined above in which the entire ring system (whether mono- orpoly-cyclic) is saturated. The term “saturated heterocyclic ring” refersto a 4- to 8-membered saturated monocyclic ring which consists of carbonatoms and one or more heteroatoms selected from N, O and S.Representative examples include piperidinyl, piperazinyl, azepanyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).

Heteroaromatics form another subset of the heterocycles; i.e., the term“heteroaromatic” (alternatively “heteroaryl”) generally refers to aheterocycle as defined above in which the entire ring system (whethermono- or poly-cyclic) is an aromatic ring system. The term“heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ringwhich consists of carbon atoms and one or more heteroatoms selected fromN, O and S. Representative examples of heteroaromatic rings includepyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (orthiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,and thiadiazolyl.

Representative examples of bicyclic heterocycles include benzotriazolyl,indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl,quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl

imidazo(2,1-b)(1,3)thiazole,

benzo-1,3-dioxolyl

In certain contexts herein,

alternatively referred to as phenyl having as a substituentmethylenedioxy attached to two adjacent carbon atoms.

Representative examples of tricyclic heterocycles includephenothiazinyl, carbazolyl, beta-carbolinyl, tetrahydro-beta-carbolinyl,acridinyl, phenazinyl, and phenoxazinyl.

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring. For example, an “unsaturatedmonocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, andbenzene.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocycle described as containing from “1 to4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4heteroatoms.

When any variable (e.g., R^(a), R^(b), R^(c), R^(k), etc.) occurs morethan one time in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “aryl which is optionallysubstituted with one or more substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

The compounds of the present invention may have asymmetric centers andmay occur, except when specifically noted, as mixtures of stereoisomersor as individual diastereomers, or enantiomers, with all isomeric formsbeing included in the present invention.

The N-substituted hydroxypyrimidinone compounds of the present inventionmay also occur as tautomers thereof. It is understood that the presentinvention includes all tautomers of the hydroxypyrimidinone compounds ofFormula I, both singly and in mixtures.

The compounds of the present invention are useful in the inhibition ofHIV integrase, the prevention or treatment of infection by humanimmunodeficiency virus (HIV) and the prevention, treatment or the delayin the onset of consequent pathological conditions such as AIDS.Preventing AIDS, treating AIDS, delaying the onset of AIDS, orpreventing or treating infection by HIV is defined as including, but notlimited to, treatment of a wide range of states of HIV infection: AIDS,ARC (AIDS related complex), both symptomatic and asymptomatic, andactual or potential exposure to HIV. For example, the compounds of thisinvention are useful in treating infection by HIV after suspected pastexposure to HIV by such means as blood transfusion, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

Compounds representative of the present invention have been tested forinhibition in an assay for the strand transfer activity of integrase.The assay is conducted in accordance with Wolfe, A. L. et al., J. Virol.1996, 70: 1424-1432, for recombinant integrase, except that: (i) theassay uses preassembled integrase strand transfer complexes; (ii) thestrand transfer reaction is performed in the presence of inhibitor in2.5 mM MgCl₂ using 0.5 to 5 nM of a 3′ FITC labeled target DNA substrateas described in WO 02/30930 and (iii) strand transfer products aredetected using an alkaline phosphatase conjugated anti-FITC antibody anda chemiluminescent alkaline phosphatase substrate. Representativecompounds (e.g., the compounds set forth in Table 1 below) tested in theintegrase assay demonstrated IC₅₀'s of about 5 micromolar or less.

Further description on conducting the assay using preassembled complexesis found in Hazuda et al., J. Virol. 1997, 71: 7005-7011; Hazuda et al.,Drug Design and Discovery 1997, 15: 17-24; and Hazuda et al., Science2000, 287: 646-650.

Certain compounds representative of the present invention have also beentested in an assay for inhibition of acute HIV infection of T-lymphoidcells, conducted in accordance with Vacca, J. P. et al., Proc. Natl.Acad. Sci. USA 1994, 91: 4096. These compounds demonstrated IC₉₅'s ofabout 20 micromolar or less.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. When the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof caninclude alkali metal salts (e.g., sodium or potassium salts), alkalineearth metal salts (e.g., calcium or magnesium salts), and salts formedwith suitable organic ligands such as quaternary ammonium salts. Also,in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify thesolubility or hydrolysis characteristics of the compound.

For the purpose of preventing or treating HIV infection or preventing,treating or delaying the onset of AIDS, the compounds of the presentinvention may be administered orally, parenterally (includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques), by inhalation spray, or rectally, inthe form of a unit dosage of a pharmaceutical composition containing atherapeutically effective amount of the compound and conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound or a prodrug of the compound to the individual in need oftreatment. When a compound of the invention or a prodrug thereof isprovided in combination with one or more other active agents (e.g.,antiviral agents useful for treating HIV infection or AIDS),“administration” and its variants are each understood to includeconcurrent and sequential provision of the compound or prodrug and otheragents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombining the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (alternatively referred to herein as “patient”) asused herein refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated. When the active compound (i.e., activeingredient) is administered as the salt, references to the amount ofactive ingredient are to the free acid or free base form of thecompound.

The pharmaceutical compositions may be in the form oforally-administrable suspensions or tablets or capsules, nasal sprays,sterile injectible preparations, for example, as sterile injectibleaqueous or oleagenous suspensions or suppositories. These compositionscan be prepared by methods and contain excipients which are well knownin the art. Suitable methods and ingredients are described inRemington's Pharmaceutical Sciences, 18^(th) edition, edited by A. R.Gennaro, Mack Publishing Co., 1990, which is herein incorporated byreference in its entirety.

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One preferred dosage range is 0.01to 500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreagents useful in the treatment of HIV infection or AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more of the HIV/AIDS antivirals,imunomodulators, antiinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable antiviral agents include those listed in thefollowing Table:

ANTIVIRALS Manufacturer (Tradename and/or Drug Name Location) Indication(Activity) abacavir Glaxo Welcome HIV infection, AIDS, ARC GW 1592(ZIAGEN ®) (nRTI) 1592U89 abacavir + lamivudine + zidovudineGlaxoSmithKline HIV infection, AIDS, ARC (TRIZIVIR ®) (nnRTI) acemannanCarrington Labs ARC (Irving, TX) ACH 126443 Achillion Pharm. HIVinfections, AIDS, ARC (nucleoside reverse transcriptase inhibitor)acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combinationwith AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 TanoxBiosystems HIV infection, AIDS, ARC adefovir dipivoxil Gilead HIVinfection, AIDS, ARC GS 840 (RTI) AL-721 Ethigen ARC, PGL, HIV positive,(Los Angeles, CA) AIDS alpha interferon Glaxo Wellcome Kaposi's sarcoma,HIV, in combination w/Retrovir AMD3100 AnorMed HIV infection, AIDS, ARC(CXCR4 antagonist) amprenavir Glaxo Wellcome HIV infection, AIDS, 141W94 (AGENERASE ®) ARC (PI) GW 141 VX478 (Vertex) ansamycin AdriaLaboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) antibodywhich neutralizes Advanced Biotherapy AIDS, ARC pH labile alpha aberrantConcepts (Rockville, Interferon MD) AR177 Aronex Pharm HIV infection,AIDS, ARC atazanavir (BMS 232632) Bristol-Myers-Squibb HIV infection,AIDS, ARC (ZRIVADA ®) (PI) beta-fluoro-ddA Nat'l Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection,AIDS, (CGP-73547) Novartis ARC (PI) BMS-234475 Bristol-Myers Squibb/ HIVinfection, AIDS, (CGP-61755) Novartis ARC (PI) capravirine Pfizer HIVinfection, AIDS, (AG-1549, S-1153) ARC (nnRTI) CI-1012 Warner-LambertHIV-1 infection cidofovir Gilead Science CMV retinitis, herpes,papillomavirus curdlan sulfate AJI Pharma USA HIV infectioncytomegalovirus immune MedImmune CMV retinitis globin cytovene Syntexsight threatening CMV ganciclovir peripheral CMV retinitis delavirdinePharmacia-Upjohn HIV infection, AIDS, (RESCRIPTOR ®) ARC (nnRTI) dextranSulfate Ueno Fine Chem. Ind. AIDS, ARC, HIV Ltd. (Osaka, Japan) positiveasymptomatic ddC Hoffman-La Roche HIV infection, AIDS, ARC (zalcitabine,(HIVID ®) (nRTI) dideoxycytidine) ddI Bristol-Myers Squibb HIVinfection, AIDS, ARC; Dideoxyinosine (VIDEX ®) combination with AZT/d4T(nRTI) DPC 681 & DPC 684 DuPont HIV infection, AIDS, ARC (PI) DPC 961 &DPC 083 DuPont HIV infection AIDS, ARC (nnRTRI) emvirine TrianglePharmaceuticals HIV infection, AIDS, ARC (COACTINON ®) (non-nucleosidereverse transcriptase inhibitor) EL10 Elan Corp, PLC HIV infection(Gainesville, GA) efavirenz DuPont HIV infection, AIDS, (DMP 266)(SUSTIVA ®) ARC (nnRTI) Merck (STOCRIN ®) famciclovir Smith Kline herpeszoster, herpes simplex emtricitabine Triangle Pharmaceuticals HIVinfection, AIDS, ARC FTC (COVIRACIL ®) (nRTI) Emory University emvirineTriangle Pharmaceuticals HIV infection, AIDS, ARC (COACTINON ®)(non-nucleoside reverse transcriptase inhibitor) HBY097 Hoechst MarionRoussel HIV infection, AIDS, ARC (nnRTI) hypericin VIMRx Pharm. HIVinfection, AIDS, ARC recombinant human Triton Biosciences AIDS, Kaposi'ssarcoma, interferon beta (Almeda, CA) ARC interferon alfa-n3 InterferonSciences ARC, AIDS indinavir Merck (CRIXIVAN ®) HIV infection, AIDS,ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC(PI) ISIS 2922 ISIS Pharmaceuticals CMV retinitis JE2147/AG1776 AgouronHIV infection, AIDS, ARC (PI) KNI-272 Nat'l Cancer Institute HIV-assoc.diseases lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, (EPIVIR ®)ARC; also with AZT (nRTI) lobucavir Bristol-Myers Squibb CMV infectionlopinavir (ABT-378) Abbott HIV infection, AIDS, ARC (PI) lopinavir +ritonavir Abbott (KALETRA ®) HIV infection, AIDS, ARC (ABT-378/r) (PI)mozenavir AVID (Camden, NJ) HIV infection, AIDS, ARC (DMP-450) (PI)nelfinavir Agouron HIV infection, AIDS, (VIRACEPT ®) ARC (PI) nevirapineBoeheringer HIV infection, AIDS, Ingleheim ARC (nnRTI) (VIRAMUNE ®)novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) pentafusaideTrimeris HIV infection, AIDS, ARC T-20 (fusion inhibitor) peptide TPeninsula Labs AIDS octapeptide (Belmont, CA) sequence PRO 542 ProgenicsHIV infection, AIDS, ARC (attachment inhibitor) PRO 140 Progenics HIVinfection, AIDS, ARC (CCR5 co-receptor inhibitor) trisodium Astra Pharm.Products, CMV retinitis, HIV infection, phosphonoformate Inc other CMVinfections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (PI)probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech HIVinfection, AIDS, (Houston TX) ARC ritonavir Abbott HIV infection, AIDS,(ABT-538) (RITONAVIR ®) ARC (PI) saquinavir Hoffmann-LaRoche HIVinfection, AIDS, (FORTOVASE ®) ARC (PI) stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, ARC didehydrodeoxy- (ZERIT ®) (nRTI)thymidine T-1249 Trimeris HIV infection, AIDS, ARC (fusion inhibitor)TAK-779 Takeda HIV infection, AIDS, ARC (injectable CCR5 receptorantagonist) tenofovir Gilead (VIREAD ®) HIV infection, AIDS, ARC (nRTI)tipranavir (PNU-140690) Boehringer Ingelheim HIV infection, AIDS, ARC(PI) TMC-120 & TMC-125 Tibotec HIV infections, AIDS, ARC (nnRTI) TMC-126Tibotec HIV infection, AIDS, ARC (PI) valaciclovir Glaxo Wellcomegenital HSV & CMV infections virazole Viratek/ICN (Costa asymptomaticHIV positive, ribavirin Mesa, CA) LAS, ARC zidovudine; AZT GlaxoWellcome HIV infection, AIDS, ARC, (RETROVIR ®) Kaposi's sarcoma incombination with other therapies (nRTI) PI = protease inhibitor nnRTI =non-nucleoside reverse transcriptase inhibitor nRTI = nucleoside reversetranscriptase inhibitor

A compound of the present invention can also be administered incombination with another HIV integrase inhibitor such as a compounddescribed in WO 99/62513, WO 99/62520, or WO 99/62897. A compound of thepresent invention can also be administered in combination with a CCR5receptor antagonist, such as a compound described in WO 99/04794, WO99/09984, WO 99/38514, WO 00/59497, WO 00/59498, WO 00/59502, WO00/59503, WO 00/76511, WO 00/76512, WO 00/76513, WO 00/76514, WO00/76792, or WO 00/76793. The compounds of this invention may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of one or moreHIV/AIDS antivirals, immunomodulators, antiinfectives, or vaccinesuseful for treating HIV infection or AIDS disclosed in the Table in WO01/38332, which is herein incorporated by reference in its entirety.

It will be understood that the scope of combinations of the compounds ofthis invention with HIV/AIDS antivirals, immunomodulators,anti-infectives or vaccines is not limited to those listed above orlisted in the above-referenced Table in WO 01/38332, but includes inprinciple any combination with any pharmaceutical composition useful forthe treatment of AIDS. The HIV/AIDS antivirals and other agents willtypically be employed in these combinations in their conventional dosageranges and regimens as reported in the art, including the dosagesdescribed in the Physicians' Desk Reference, 54^(th) edition, MedicalEconomics Company, 2000. The dosage ranges for a compound of theinvention in these combinations are the same as those set forth above.

Abbreviations used in the instant specification, particularly theSchemes and Examples, include the following:

-   -   AIDS=acquired immunodeficiency syndrome    -   ARC=AIDS related complex    -   BOC or Boc=t-butyloxycarbonyl    -   Bn=benzyl    -   Bz=benzoyl    -   CBZ or Cbz=carbobenzoxy (alternatively, benzyloxycarbonyl)    -   DMAD=dimethylacetylenedicarboxylate    -   DMAP=dimethylaminopyridine    -   DMF=N,N-dimethylfonmamide    -   Et=ethyl    -   EtOAc=ethyl acetate    -   FIA-MS=flow injection analysis mass spectrometry    -   HIV=human immunodeficiency virus    -   HPLC=high performance liquid chromatography    -   m-CPBA=meta-chloroperbenzoic acid    -   Me=methyl    -   NMP=N-methyl pyrrolidinone    -   NMR=nuclear magnetic resonance    -   Ph=phenyl    -   TFA=trifluoroacetic acid    -   TBF=tetrahydrofuran

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials and reagents. Inthese reactions, it is also possible to make use of variants which arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail. Furthermore, other methods for preparingcompounds of the invention will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. Unless otherwise indicated, all variables are as definedabove.

The compounds of the present invention can be prepared by couplingsuitable substituted alkyl1-alkyl-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylates (orcarboxylic acids or halides) with the appropriate amines, as representedby Scheme 1. In the scheme, P is H or a protective group, typically anester (e.g., benzoate or pivalate) that is normally removed under theconditions employed to convert the the methyl ester to the amide. Theester protective group is typically used to purify the 2-substituted-5,6dihydroxypyrimidine-4-carboxylates after their synthesis when theunprotected product cannot be crystallized from the reaction crudeand/or for synthetic reasons.

Methods for coupling carboxylic acid derivatives with amines to formcarboxamides are well known in the art. Suitable methods are described,for example, in Jerry March, Advanced Organic Chemistry, 3rd edition,John Wiley & Sons, 1985, pp. 370-376. Amines of formula 1-1 can beprepared using the methods described in Richard Larock, ComprehensiveOrganic Transformations, VCH Publishers Inc, 1989, pp. 385-438, orroutine variations thereof.

Methyl 1-alkyl-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylates offormula 1-2 can be prepared as shown in Scheme 2, wherein amidoxime 2-1can be reacted with DMAD in an appropriate solvent and at a suitabletemperature to give the intermediate dihydroxypyrimidine 2-2, followedby protection of the 5-hydroxy group in 2-2 with a suitable protectingagent such as benzoate or pivalate to give 2-3, and then alkylation ofnitrogen-1 to afford 1-2. This procedure is described in the literature[Culbertson et al., J Heterocycl. Chem. 1979, 16 (7): 1423-24].Dihydroxypyrimidine 2-2 can be isolated or directly protected to give2-3. The alkyl group can be introduced on N₁ by reaction of 2-3 with analkylating agent in the presence of an inorganic base (e.g., cesiumcarbonate). If a mixture of N- and O-alkylated derivatives results, thedesired N-alkylated product 1-2 can be separated by flashchromatography. Scheme 2 is exemplified in Example 1.

Methyl 1-alkyl-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylates offormula 1-2 can be prepared as shown in Scheme 3, wherein anN-alkylamidoxime 3-1 can be reacted with dimethylacetylenedicarboxylateto give the unprotected 1-2 (P═H). The unprotected-compound can beisolated as such or it can be converted to 1-2 by reaction with asuitable protecting group. Scheme 3 is exemplified in Example 2.

Amidoximes 2-1 and 3-1 are prepared from the corresponding nitrites bychemistry described herein (see Example 1, Step 1 and Example 2, Step2). Nitriles can be prepared from carboxylic acids by various proceduresknown in the art, including, for example, conversion to carboxamides bythe procedure of of Pozdnev (Tetrahedron Lett. 1989, 30: 5193) (seealso, Example 6, Step 2), and dehydration of the amide by the procedureof Waldmann (Tetrahedron 1994, 50: 11865) (see also, Example 6, Step 3).

Compounds of the present invention of general formula 3-3 or 3-6 can beprepared in accordance with Scheme 3, Parts 1 and 2, whereinhaloderivative 3-1 or 3-4 can be synthesized by the bromination orchlorination of a suitable substrate affording a —CH₂Br, —CH₂Cl, —CHBr-,or —CHCl— group, followed by displacement of the halogen with anucleophile (“Nu”) such as an amine, thiol, or alcoholate to obtain thenucleophile-substituted methyl ester intermediate 3-2 or 3-5, which neednot be isolated. Elaboration of the methyl ester functionality into thecarboxamide will afford the final product 3-3 or 3-6. Scheme 3 isexemplified in Example 5.

Scheme 4 depicts the preparation of compounds of the invention thatcontain an alkylated aliphatic amine in the substituent at the 2position. Nitrogen alkylation is achieved via a reductive amination oralkylation. The nitrogen alkylation can be performed before formation ofthe amide (via 4-3) or after formation of the amide (via 4-2) dependingon the substrate, with suitable deprotection as necessary. Scheme 4 isexemplified in Examples 6 to 8 below.

Compounds of the present invention with general formula 5-3 containingan acylated nitrogen or sulfonylated nitrogen in the substituent at the2-position, can be prepared following Scheme 5. Acylation orsulfonylation of the nitrogen in the 2-substituent of the pyrimidinecore provides compound 5-2, which can be elaborated into the final amide5-3 by reaction of a suitable amine in a polar solvent. Scheme 5 isexemplified in Examples 9 to 12 below.

The preparation of compounds that feature a carboxamide at the 2position of the pyrimidine core can be achieved as shown in Scheme 6,wherein a starting material bearing a 2-ethyl- and a 4-methylcarboxylatefunctionality (6-1) is employed. This strategy will allow theregioselective elaboration of the 4-methyl ester into the carboxamide byreaction with a suitable amine. The other ester bond in the 2 positioncan then be further elaborated. Scheme 6 is exemplified in Example 13below.

Compounds of the present invention of formula 7-2 can be prepared byreaction of aldehydes or ketones 7-1 with suitable amines underreductive alkylation conditions, as shown in Scheme 7. Scheme 7 isexemplifed in Example 14 below.

In the processes for preparing compounds of the present invention setforth in the foregoing schemes and exemplified in the examples below,functional groups in various moieties and substituents may be sensitiveor reactive under the reaction conditions employed and/or in thepresence of the reagents employed. Such sensitivity/reactivity caninterfere with the progress of the desired reaction to reduce the yieldof the desired product, or possibly even preclude its formation.Accordingly, it may be necessary or desirable to protect sensitive orreactive groups on any of the molecules concerned. Protection can beachieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973 and in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Theprotecting groups can be removed at a convenient subsequent stage usingmethods known in the art. For example, in preparing the compounds of theinvention it is sometimes necessary to protect one or more amino groups(e.g., amino groups present in substituents at the 2-position of thepyrimidinone ring) with, for example, a Boc or Cbz group or to protecthydroxy (e.g., the 5-hydroxy group on the pyrimidinone ring) with, forexample, a benzoyl or benzyl group. The Boc group can be removed by acidtreatment (e.g., TFA) either before or after formation of the finalamide at C-6 of the pyrimidinone nucleus. The Cbz and benzyl groups aretypically removed by catalytic hydrogenation or under strong acidconditions, either prior to or following formation of the final amide.The benzoyl group can be removed concurrently with the formation of thefinal amide. Examples 6 and 12 below illustrate the use of a Bocprotective group and of Boc, benzoyl and benzyl protective groups in thepreparation of compounds of the invention.

The preparation of compounds that feature a bis oxalamide at the 2position of the pyrimidine core can be achieved as shown in Scheme 8,wherein a starting material bearing a basic nitrogen at the 2-positionof the pyrimidine carboxyamide (8-1) is employed. This strategy willallow to obtain the final compound (8-3) following two possibleprocedures: by simple coupling of monoamide oxalic acid to the amine(8-1) or by the acylation of the basic nitrogen of (8-1) with dimethyloxalate to give the ester intermediate (8-2) that is converted to thefinal compound by heating in presence of amine in appropriate solvent.Scheme 8 is exemplified in Examples 17, 18, and 20 below.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 1 Methyl5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Step 1:Tert-butyl-2-[amino(hydroxyimino)methyl]pyrrolidine-1-carboxylate

A solution of hydroxylamine hydrochloride (1.0 eq.) in MeOH was added at0° C. to a solution of KOH (1.0 eq.) in MeOH. The resulting reactionmixture was filtered and added to a solution oftert-butyl-2-cyanopyrrolidine-1-carboxylate (1.0 eq.) in methanol andstirred at 40° C. for 2 h. The solvent was removed in vacuo and theresidue treated with water; the solid was filtered and washed with amixture of Et₂O: Petroleum Ether 1:1 to afford the title compound as awhite solid as a mixture of rotamers by NMR.

¹H-NMR (DMSO-d₆, 400 MHz) δ 8.92 (s, 1 H), 5.35 (s, 1 H), 5.15 (s, 1 H),4.25 (bs, 0.5 H), 4.10 (s, 0.5 H), 3.40-3.30 (m, 1 H), 2.10-1-70 (m, 4H), 1.40 (s, 4.5 H), 1.35 (s, 4.5 H), one signal is obscured by water.

Step 2: Methyl5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate

A solution of the product of Step 1 (1.0 eq.) and dimethylacetylenedicarboxylate (1.05 eq.) in CHCl₃ was refluxed for 3 h. Thereaction mixture was concentrated and the crude product was useddirectly in the next step without further purification. The crudeproduct was dissolved in xylene and refluxed for 24 h. The solvent wasremoved in vacuo and the crude was dissolved in pyridine. Benzoicanhydride was added (1.5 eq.). The reaction mixture was stirred at roomtemperature until the starting material was consumed as determined by MSanalysis. The reaction mixture was concentrated, and the resulting oilwas diluted with ethyl acetate and washed with 1N HCl solutionssaturated NaHCO₃ solution, saturated NaCl solution. The crude oilobtained after organic solvent evaporation was purified by flashchromatography to obtain the title compound as a yellow solid.

¹H-NMR (CDCl₃, 400 MHz) δ 12.08 (bs, 1 H), 8.18 (d, J=7.6 Hz, 2 H), 7.64(t, J=7.4 Hz, 1 H), 7.50 (t, J=7.6 Hz, 2 H), 4.80-4.60 (m, 1 H), 3.82(s, 3 H), 3.60-3.50 (m, 1 H), 3.40-3.20 (m, 1 H), 2.50-2.10 (m, 2 H),2.00-1.70 (m, 2 H), 1.50 (s, 9 H).

MS m/z 444 (M+H)⁺.

Step 3: Methyl5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

To a stirred solution of the product of Step 2 (1.0 eq.) in THF, Cs₂CO₃was added (1.2 eq.) followed by the addition of CH₃I (2.0 eq.). Thereaction was stirred at 40° C. until the starting material was consumedas determined by MS analysis. The reaction was concentrated and theresidue taken up with EtOAc, washed with 1 N HCl, saturated solution ofNaHCO₃ and brine. The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated. Reaction crude showed 3.4:1 ratio N (desiredproduct) versus O methylation. The title product was purified by flashcolumn chromatography (EtOAc:Petroleum Ether=1:1) and obtained as a 1:1mixture of rotamers by NMR.

¹H-NMR (CDCl₃, 400 MHz) δ 8.12 (d, J=7 Hz, 2 H), 7.58 (t, J=7 Hz, 1 H),7.46 (t, J=7 Hz, 2 H), 4.97-4.95 (m, 0.5 H), 4.87-4.83 (m, 0.5 H), 3.74(s, 1.5 H), 3.72 (s, 1.5 H), 3.63 (s, 1.5 H), 3.59 (s, 1.5 H), 3.56-3.42(m, 1 H), 2.40-2.25 (m, 5 H), 1.41 (s, 4.5 H), 1.25 (s, 4.5 H).

MS m/z 458 (M+H)⁺.

Also obtained was the O-methylated compound of formula:

as a mixture of rotamers by NMR. ¹H-NMR (CDCl₃, 400 MHz) δ 8.21 (d,J=7.6 Hz, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 2H), 5.10-5.05(m, 0.3H), 5.00-4.95 (m, 0.7H), 4.01 (s, 3H), 3.87 (s, 3H), 3.80-3.60(m, 2H), 2.50-2.40 (m, 1H), 2.15-2.00 (m, 2H), 2.00-1.85 (m, 1H), 1.61(s, 2.7H), 1.40 (s, 6.3H).

MS m/z 458 (M+H)⁺.

EXAMPLE 2 Benzyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]indoline-1-carboxylate

Step 1: Benzyl2-[[hydroxy(methyl)amino](imino)methyl]indoline-1-carboxylate

1-Benzyloxycarbonyl-2-cyanoindoline was added to a solution oftriethylamine (2 eq.) and MeNHOH.HCl (2 eq.) in EtOH. After stirringovernight the reaction mixture was evaporated, dissolved in EtOAc,washed with water, dried over Na₂SO₄ and evaporated to afford the titlecompound.

¹H NMR (DMSO-d₆, 340K, 300 MHz) δ 7.68 (d, J=8.0 Hz, 1 H), 7.41-7.30 (m,5H), 7.19 (t, J=7.5 Hz, 2 H), 6.99 (t, J=7.6 Hz, 1 H), 5.53 (dd, J=5.5,10.9 Hz, 1 H), 5.22 (s, 2 H), 3.62 (dd, J=11.0, 16.6 Hz, 1 H), 3.33 (s,3 H), 3.01 (dd, J=5.5 Hz, 16.6 Hz, 1 H).

MS m/z 326 (M+H)⁺.

Step 2: Benzyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidi-2-yl]indoline-1-carboxylate

The product of Step 1 was dissolved in CHCl₃ anddimethylacetylenedicarboxylate was added dropwise (1.2 eq.) at roomtemperature. After 4 h the mixture was evaporated, and the residue wasdissolved in xylene and stirred at 160° C. for 2 days. The solvent wasthen evaporated, and the residue was dissolved in pyridine, after which(PhCO)₂O (2 eq.) was added and the reaction mixture was stirred for 2days. After evaporation, the resulting crude oil was diluted with EtOAc,washed with HCl 1N, dried over Na₂SO₄ and evaporated. The product waspurified by flash chromatography on silica gel (EtOAc/petroleum ether,1:4) to afford the title product.

¹H NMR (DMSO-d₆, 340 K, 400 MHz) δ 8.08 (d, J=7.3 Hz, 2 H), 7.77 (t,J=7.4 Hz, 2 H), 7.62 (t, J=7.6 Hz, 2 H), 7.31-7.20 (m, 7 H), 7.00 (t,J=7.3 Hz, 1H), 5.83 (dd, J=4.6 Hz, 11.0 Hz, 1 H), 5.23-5.13 (m, 2 H),3.76 (dd, J=11.1, 16.6 Hz, 1H), 3.65 (s, 3 H), 3.56 (s, 3 H), 3.27 (dd,J=4.4 Hz, 16.6 Hz, 1 H).

MS m/z 540 (M+H)⁺.

EXAMPLE 3N-(4-Fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

To a stirred solution of methyl5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate(prepared from 4-methylbenzonitrile by procedures similar to those setforth in Examples 2 or 3) in DMF 3 equivalents of 4-fluorobenzylaminewere added and mixture was stirred at 90° C. for 2 h. The title productprecipitated from the cooled reaction mixture after the addition of 2 NHCl, and was collected by filtration and washed with diethyl ether.

¹H NMR (DMSO-d₆, 400 MHz) δ 12.45 (s, 1 H), 9.31 (bt, J=6.0 Hz, 1 H),7.62 (m, 2 H), 7.40-7.32 (m, 4 H), 7.14 (t, J=8.8 Hz, 2 H), 4.45 (d,J=6.0 Hz, 2 H), 3.35 (s, 3 H), 2.48 (s, 3 H).

MS m/z 368 (M+H)⁺.

EXAMPLE 4N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: 4,5-Dihydroxy-6-(methoxycarbonyl)pyrimidine-2-carboxylic acid

2-Ethoxycarbonyl-4,5-Dihydroxy-6-(methoxycarbonyl)pyrimidine [obtainedfrom ethyl amino(hydroxyimino)ethanoate (Branco, P. S. et al,Tetrahedron 1992, 40: 6335) by procedures similar to those set forth inExample 1] was suspended in dioxane/THF 2:1 and 1N NaOH was added. After20 min the mixture was acidified with 1N HCl solution, concentrated andfiltered to give the title product.

¹H-NMR (DMSO-d, 400 MHz) δ 13.10 (bs, 1 H), 11.11 (bs, 1 H), 3.82 (s, 3H).

MS m/z 213 (M−H)⁻.

Step 2: Methyl 5,6-dihydroxypyrimidine-4-carboxylate

A solution of the product of Step 1 in HCl 1N solution was stirred for 6hours at 90° C. Reaction mixture was filtered and the solid washed withHCl 1N. Evaporation of the filtrate afforded the title product as asolid.

¹H NMR (DMSO-d₆, 300 K, 400 MHz) δ 7.75 (s, 1 H), 3.82 (s, 3 H). ¹³C NMR(DMSO-d₆, 300 K, 400 MHz) δ 165.66, 158.20, 147.14, 139.00, 127.85,52.16.

Step 3: Methyl5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxypyrimidine-4-carboxylate

Pivaloyl chloride 1.1 eq. was added to a solution of the product of Step2 in pyridine, and the mixture was heated to 40° C. for 10 minutes. HPLCshowed the complete conversion of starting material. The reactionmixture was concentrated, the resulting oil was diluted with ethylacetate and washed with 1 N HCl solution. The title product was obtainedas a brown solid after evaporation of the organic phase and triturationwith diethyl ether.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.35 (s, 1 H), 8.18 (s, 1 H), 3.85 (s, 3H), 1.28 (s, 9 H).

Step 4: Methyl5-[(2,2-dimethylpropanoyl)oxy]1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Dimethyl sulfate (1.5 eq.) was added to a solution of the product ofStep 3 (1 eq.) in THF containing cesium carbonate (1.5 eq.). Thereaction was carried out at 50° C. for thirty minutes. The solvent wasevaporated and the resulting oil was dissolved in ethyl acetate, washedwith 1N HCl solution. The crude title compound was recovered as yellowsolid and used in the next step without purification.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.43 (s, 1 H), 3.81 (s, 3 H), 3.45 (s, 3 H),1.30 (s, 9 H).

Step 5:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

4-Fluorobenzylamine (3 eq.) was added to a solution of the crude productof Step 4 in DMF and the reaction mixture was heated to 90° C. for onehour. The title compound was obtained by RP-HPLC (C₁₈, eluting withwater and acetonitrile containing 0.1% TFA).

¹H NMR (DMSO-d₆, 400 MHz) δ 12.5 (s, 1 H), 9.54 (t, J=6.2 Hz, 1 H), 8.05(s, 1H), 7.36 (dd, J=6.2, 8.4 Hz, 2 H), 7.14 (t, J=8.4 Hz, 2 H), 4.45(d, J=6.2 Hz, 2 H), 3.44 (s, 3 H).

MS m/z 276 (M−H)⁻.

EXAMPLE 5N-(4-Fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl2-[4-(bromomethyl)phenyl]-5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

To a vigorously boiling solution of methyl5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylatein carbon tetrachloride N-bromosuccinimide (1 eq.) and benzoyl peroxide(0.05 eq.) were added as dry powders. After 4 hr the mixture was allowedto reach room temperature and the precipitated succinimide was filteredoff. The filtrate was evaporated under vacuum and the solid residue wasused as such.

¹H NMR (DMSO-d₆, 400 MHz) δ 7.68-7.57 (m, 4 H), 4.77 (s, 2 H), 3.80 (s,3 H), 3.27 (s, 3 H), 1.30 (s, 9 H).

Step 2:N-(4-Fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide

A THF solution of methyl2-[4-(bromomethyl)phenyl]-5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylatewas reacted with 4 eq. of morpholine for 0.5 h at room temperature.After evaporation of volatiles, the oily residue was taken into DMF andtreated with 3 eq. of 4-fluorobenzylamine at 90° C. for 2 h. Titleproduct was isolated as its trifluoroacetate salt by RP-HPLC (C18,water/acetonitrile with 1% of TFA as eluant).

¹H-NMR (DMSO-d₆, 400 MHz) δ 12.45 (s, 1 H), 10 (bs, 1 H), 9.31 (bt, 1H), 7.74 (m, 2 H), 7.62 (m, 2 H), 7.35 (m, 2 H), 7.14 (t, J=8.8 Hz, 2H), 4.54-4.38 (m, 4 H), 4.1-3.9 (m, 2 H), 3.9-3.7 (m, 2 H), 3.68-3.51(m, 2 H), 3.31 (s, 3 H), 3.2-3.1 (m, 2 H).

MS: m/z 453 (M+H)⁺.

EXAMPLE 6N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: 4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acid

To a vigorously stirred solution of 3-morpholinecarboxylic acid andtriethylamine (1.11 eq.) in MeOH (1.4 M) at 50° C. was added di-t-butyldicarbonate (2 eq.). Stirring was continued at 50° C. for 5 min and atroom temperature overnight. The reaction mixture was then concentratedto obtain an oily residue and suspended between EtOAc (500 ml) andsaturated NaHCO₃ (500 ml). The organic layer was extracted withsaturated NaHCO₃ (2×250 ml) and H₂O (250 ml). Combined aqueous layerswere brought to pH=2.0 with 3 M HCl and immediately extracted with EtOAc(2×500 ml). The combined organic layers were washed with dilute HCl,dried, filtered and evaporated to give the title compound as a paleyellow oil, a 1:1 mixture of rotamers by NMR.

δ ¹H NMR (400 MHz, DMSO-d₆) 12.93 (bs, 1 H), 4.32 (s, 0.5 H), 4.29 (s,0.5 H), 4.2-4.1 (m, 1 H), 3.83-3.74 (m, 1 H), 3.58-3.52 (m, 2 H),3.36-3.31 (m, 1 H), 3.16 (t, J=11.4 Hz, 0.5 H), 3.00 (t, J=11.4 Hz, 0.5H), 1.40 (s, 4.5 H), 1.36(s, 4.5 H).

MS m/z 232 (M+H)⁺.

Step 2: tert-Butyl 3-(aminocarbonyl)morpholine-4-carboxylate

To a stirred solution of the compound prepared in Step 1 (1 eq.),pyridine (0.6 eq.) and di-t-butyl dicarbonate (1.3 eq.) in dioxane (0.6M), NH₄HCO₃ (1.26 eq.) was added and the mixture was stirred at roomtemperature for 20 hours. Mixture was concentrated, taken up in EtOAcand washed with water and brine. Organics were dried over Na₂SO₄ andevaporated giving the title product as an oil which crystallized at roomtemperature.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.35 (bs, 1 H), 7.06 (bs, 1 H), 4.15 (bs, 2H), 3.76 (bs, 1 H), 3.57-3.51 (m, 2 H), 3.28 (m, 1 H), 3.18 (m, 1 H),1.36 (s, 9 H).

MS m/z 231 (M+H)⁺.

Step 3: tert-Butyl 3-cyanomorpholine-4-carboxylate

A solution of the product of Step 2 (1 eq.) and triethylamine (2.1 eq.)in CH₂Cl₂ (0.1 M) was cooled to 0° C. and trifluoroacetic anhydride (1.1eq.) added dropwise under nitrogen. Stirring was continued 3.5 hoursmore at room temperature and volatiles removed in vacuo. Residues takenin EtOAc were washed with water, brine and dried over Na₂SO₄.Evaporation gave the title compound as a brown solid.

¹H NMR(DMSO-d₆, 400 MHz) δ 5.04(d, J=2.7 Hz, 1 H), 3.96 (d, J=12.2 Hz,1H), 3.86 (dd, J=11.5, 2.6 Hz, 1 H), 3.69 (d, J=12.4 Hz, 1 H), 3.56 (dd,J=12.2, 3.2 Hz, 1H), 3.40 (td, J=11.9, 2.89 Hz, 1 H), 2.97 (m, 1 H),1.43 (s, 9 H).

MS m/z 213 (M+H)⁺.

Step 4: tert-Butyl3-[(Z)-amino(hydroxyimino)methyl]morpholine-4-carboxylate

A solution of the product of Step 3 (1 eq.), hydroxylamine hydrochloride(1.4 eq.) and triethylamine (1.7 eq.) in EtOH (0.5 M) was refluxed undernitrogen for 5 hours. Mixture was concentrated and residues taken up inEtOAc and washed with water and brine. Combined organics were dried overNa₂SO₄ and evaporated giving the title compound as a yellow solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.16 (bs, 1 H), 5.32 (bs, 2 H), 4.30 (bs, 1H), 4.08 (d, J=11.6 Hz, 1 H), 3.75 (d, J=6.8 Hz, 1 H), 3.50-3.33 (m, 4H), 1.38 (s, 9 H).

MS: m/z 246 (M+H)⁺.

Step 5:Dimethyl-2-({2-amino-2-[4-(tert-butoxycarbonyl)morpholin-3-yl]ethenyl}oxy)but-2-enedioate

A solution of the product of Step 4 (1 eq.) anddimethylacetylenedicarboxylate (1.2 eq.) in CHCl₃ was refluxed for 1hour under nitrogen and solution concentrated. Residue was purified byflash chromatography on silica gel, eluents petroleum ether/EtOAc7:3->1:1, to give the desired product as a mixture of two isomers E/Z(76:14).

¹H NMR (DMSO-d₆, 400 MHz, 300K) δ 6.60 and 6.20 (2 bs, 2 H), 5.58 and5.41 (2s, 1 H), 4.36 (bs, 1 H), 4.04 (bs, 1 H), 3.8 (bs, 1 H), 3.76 and3.72 (2 s, 3 H), 3.63 and 3.58 (2 s, 3 H), 3.53 (td, J=13.6, 3.7 Hz, 1H), 3.44 (t, J=10.4 Hz, 1 H), 3.31 (m, 2 H), (s, 9 H).

MS m/z 388 (M+H)⁺.

Step 6:tert-Butyl-3-[4,5-dihydroxy-6-(methoxycarbonyl)pyrimidin-2-yl-]morpholine-4-carboxylate

The adducts of Step 5 were refluxed in xylenes for 24 hours. Then thereaction was cooled down and concentrated in vacuo. Ethyl ether wasadded until precipitation of a solid that was filtered, washed withethyl ether and dried to give the title pyrimidine as an orange solid.

¹H NMR (DMSO-d₆, 400 MHz, 340 K) δ 4.62 (s, 1H), 4.15 (d, J=12 Hz, 1H),3.84 (bs, 1H), 3.82 (s, 3H), 3.70 (dd, J=12.3, 4 Hz, 1H), 3.61 (dd,J=12.2, 3.8 Hz, 1H), 3.56 (t, J=13 Hz, 1H), 3.43 (td, J=11.5, 3.4 Hz,1H), 1.35 (s, 9H).

MS m/z 356 (M+H)⁺.

Step 7:tert-Butyl-3-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]morpholine-4-carboxylate

The pyrimidine from Step 6 in dry pyridine (0.2 M), was treated withbenzoic anhydride (2 eq.) overnight at room temperature. The mixture wasevaporated, taken in EtOAc and washed with HCl 1N, NaHCO₃ and brine.Organics were dried over Na₂SO₄, and filtered, evaporated and purifiedby flash chromatography on silica gel, eluents EtOAc/Petioleum Ether:7/3.

¹H NMR (DMSO-d₆, 300 MHz, 340K) δ 13.3 (bs, 1 H), 8.07 (d, J=7.5 Hz,2H), 7.76 (t, J=7.5 Hz, 1 H), 7.61 (t, J=7.5 Hz, 2 H), 4.73 (s, 1 H),4.22 (d, J=12.4 Hz, 1 H), 3.86 (d, J=11.0 Hz, 1H), 3.78 (dd, J=12.4, 3.9Hz, 1 H), 3.73 (s, 3 H), 3.58 (t, J=13.9 Hz, 2 H), 3.47 (td, J=10.7,3.6, 1 H), 1.36 (s, 9 H).

MS m/z 600 (M+H)⁺.

Step 8: Alkylated Derivatives 8A and 8B

The pyrimiidine product of Step 7 in dry THF (0.6 M) was treated withcesium carbonate (1.5 eq.) and dimethyl sulfate (1.5 eq.) at 50° C. for1 hour. Solvent was removed in vacuo and residue taken in EtOAc, washedwith HCl 1N and brine. Organics were dried over Na₂SO₄, filtered andevaporated to obtain a crude which was purified by flash chromatographyon silica gel, (eluents EtOAc/Petroleum Ether: 3/7) to separate the twocompounds 8A and 8B (ratio 8A/8B 1/0.85).

An alternative route was also employed as follows: The pyrimidineproduct of Step 7 was added to a suspension of LiH (1.1 eq) in dioxaneat room temperature. The mixture was aged 45 min at 38° C. and was thencooled to room temperature. Dimethylsulfate (1.3 eq) was added and themixture was warmed to 38° C. (4 h) and 56° C. (4 h). The reactionmixture was cooled to 16° C. and glacial acetic acid (0.1 eq) was added,followed by water and EtOAc. The aqueous layer was separated andextracted with EtOAc. The combined organic layer was dried (Na₂SO₄) andconcentrated to an oil, which was chromatographed through silica gel,eluting with 50-55% EtOAc/hexanes to separated compound 8A from 8B. Thefractions were evaporated to a foamy solid. This solid was dissolved inether and re-evaporated to foamy solid that could be scraped out easily.This solid was dried in a vacuum oven overnight at 40° C. to afford 8Bas a pale yellow solid. The ratio of 8A/8B is variable with this route,from 1:4 to 1:12.

tert-Butyl-3-[5-(benzoyloxy)-4-methoxy-6-(methoxycarbonyl)pyrimidin-2-yl]morpholine-4-carboxylate(8A)

¹H NMR (300 MHz, DMSO-d₆+TFA, 330K) δ 8.10 (d, J=7.9 Hz, 2 H), 7.77 (t,J=7.3 Hz, 1 H), 7.61 (t, J=7.4 Hz, 2 H), 4.94 (bs, 1H), 4.50 (d, J=11.6Hz, 1H), 4.0 (s, 3H), 3.85-3.81 (m, 2 H), 3.76 (s, 3 H), 3.66 (d, J=10.4Hz, 1H), 3.49-3.45 (m, 2 H), 1.35 (bs, 9 H).

MS m/z 474 (M+H)⁺.

tert-Butyl-3-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]morpholine-4-carboxylate(8B)

¹H NMR (DMSO-d₆, 400 MHz, 330K,) δ 8.09 (d, J=7.3 Hz, 2 H), 7.77 (t,J=7.5 Hz, 1 H), 7.62 (t, J=7.8 Hz, 2 H), 5.08 (d, J=3.4 Hz, 1 H), 4.21(d, J=12.3 Hz, 1 H), 3.95-3.85 (m, 3 H), 3.76 (s, 3 H), 3.58 (s, 3 H),3.55-3.50 (m, 2 H), 1.34 (s, 9 H).

MS m/z 474 (M+H)⁺.

Step 9:tert-Butyl-3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-morpholine-4-carboxylate

The methyl ester 8B in dry MeOH was treated with 4-fluorobenzylamine(2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo andresidue triturated with Et₂O to obtain the title product.

¹H NMR (300 MHz, DMSO-d₆, 320K) δ 11.95 (bs, 1 H), 8.32 (t, J=6.0 Hz, 1H), 7.39-7.35 (m, 2 H), 7.19-7.13 (m, 2 H), 4.96 (dd, J=4.25, 2.42 Hz, 1H), 4.62 (dd, J=14.9, 6.95 Hz, 1H), 4.49 (dd, J=14.9, 5.83 Hz, 1H), 4.16(dd, J=12.2, 2.0 Hz, 1H), 3.87-3.79 (m, 2H), 3.70-3.64 (m, 1H),3.55-3.45 (m, 5H), 1.23 (s, 9H).

MS m/z 463 (M+H)⁺.

Step 10:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-morpholin-3-yl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The compound from Step 9 was treated with a mixture ofdichloromethane/TFA (2/1) for 1 hour at room temperature. Organics wereremoved in vacuo to give the title compound as a solid.

¹H NMR (300 MHz, DMSO-d₆, 300 K) δ 9.45 (bs, 1 H), 7.39-7.36 (m, 2 H),7.19-7.15 (m, 2 H), 4.93 (d, J=9.2 Hz, 1 H), 4.64 (dd, J=15.4, 6.7 Hz, 1H), 4.55 (dd, J=15.4, 6.2 Hz, 1 H), 4.35 (d, J=12.8 Hz, 1 H), 4.08 (d,J=12.6 Hz, 1 H), 3.77 (t, J=12.4 Hz, 1 H), 3.55 (s, 3 H), 3.55-3.46 (m,2 H), 3.40-3.34 (m, 1 H).

MS m/z 363 (M+H)⁺.

Step 11:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The compound from Step 10 was dissolved in MeOH and treated withtriethylamine (1 eq.), sodium acetate (1.6 eq.), formaldehyde 37% w/waq. soln. (3 eq.), and sodium cyanoborohydride (1.43 eq.). The mixturewas left stirring at room temperature for 1 hour. The reaction mixturewas concentrated and the title compound was obtained by RP-HPLCpurification (C₁₈, eluting with water and acetonitrile containing 0.1%TFA), as its trifluoroacetate salt.

¹H NMR (400 MHz, DMSO-d₆+TFA) δ 12.33 (bs, 1 H), 10.05 (bs, 1 H), 9.48(t, J=6.4 Hz, 1 H), 7.35-7.33 (m, 2 H), 7.15-7.12 (m, 2 H), 4.98 (d,J=8.8 Hz, 1 H), 4.57 (d, J=6.4 Hz, 2 H), 4.36 (d, J=12.7 Hz, 1 H), 4.13(d, J=12.4 Hz, 1 H), 3.77 (t, J=12.5 Hz, 1 H), 3.69 (d, J=12.8 Hz, 1 H),3.54 (s, 3 H), 3.48-3.41 (m, 2 H), 2.83 (s, 3 H).

MS m/z 377 (M+H)⁺.

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamidehas been resolved into its enantiomers by semi preparative chiral HPLCusing the following conditions:

-   -   Solvents: a mixture of 1:1 0.2% TFA in Hexanes:EtOH    -   Column: chiralpak AS column, 250×46 mm at 1.0 ml/min, collected        by absorbtion at 260 nM        The first eluate is the (+) enatiomer (MeOH, c=0.24, 25C):        [α]_(D)=(+) 55.42.        The second eluate is the (−) enantiomer (MeOH, c=0.215, 25C)        [α]_(D)=(−) 51.63.

EXAMPLE 72-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl1-methyl-2-(4-tert-butoxycarbonylpiperazin-2-yl))-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Methyl1-methyl-2-(4-tert-butoxycarbonyl-1-benzyloxycarbonylpiperazin-2-yl))-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate(prepared from1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (Bigge et al, Tetrahedron Lett. 1989, 30: 5193) by proceduressimilar to those set forth in Examples 2 or 3 in combination with adeprotection step) was dissolved in MeOH and hydrogenated at atmpressure on 10% Pd/C for 1 hour. The crude title product was obtainedafter filtration and evaporation.

Step 2:N-(4-fluorobenzyl)1-methyl-2-(4-tert-butoxycarbonylpiperazin-2-yl))-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The crude product from Step 1 was dissolved in MeOH and4-fluorobenzylamine (3.5 eq.) added. After being refluxed overnight, theprecipitate was filtered and washed with Et₂O to afford the titleproduct.

Step 3:N-(4-fluorobenzyl)1-methyl-2-(4-tert-butoxycarbonyl-1-methylpiperazin-2-yl))-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The solid product from Step 2 was dissolved in MeOH and NaCNBH₃ (1.4eq.), AcONa (1.6 eq.), HCHO 37% (1 eq.) were added. The reaction mixturewas stirred at room temperature for 2 days, and then evaporated toafford the crude title product.

¹H NMR (DMSOd₆+TFA, 340K, 400 MHz) δ 7.40-7.35 (m, 2H), 7.18-7.10 (m,2H), 4.83 (d, J=7.3 Hz, 1H), 4.59 (d, J=6.3 Hz, 2H), 4.41 (d, J=14.9 Hz,1H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 3.54 (s, 3H), 3.38-3.25 (m, 2H), 3.15-3.05 (m, 1H), 2.85 (s, 3H), 1.45 (s, 9H). MS (EI+) m/z=476(M+H)⁺.

Step 4:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperazin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The crude product from Step 3 was stirred in CH₂Cl₂/TFA (1:1) for 2hours to remove the Boc protective group from the piperazinyl nitrogen.

¹H NMR (DMSOd₆, 340K, 400 MHz) δ 12.25 (bs, 1H), 9.03 (bs, 1H),7.42-7.35 (m, 2H), 7.20-7.10 (m, 2H), 4.62-4.45 (m, 2H), 4.14-4.09 (m,1H), 3.62 (s, 3H), 3.62-3.52 (m, 1H), 3.48-3.32 (m, 1H), 3.25-3.15 (m,1H), 3.15-3.05 (m, 2H), 2.44-2.32 (m, 1H), 2.34 (s, 3H).

MS (EI+) m/z=376 (M+H)⁺.

Step 5:2-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Triethylamine (2 eq.), NaCNBH₃ (1.4 eq.), AcONa (1.6 eq.) and CH₃CHO (1eq.) were added to a methanolic solution of the crude product obtainedin step 4. The reaction was stirred at room temperature for 1 hour. Thetitle product was obtained as its trifluroacetate salt by preparativeRP-HPLC purification (C18, gradient of CH₃CN/H₂O+0.01% TFA).

¹H NMR (DMSO-d₆+TFA, 300 MHz) δ 9.40 (t, J=5.9 Hz, 1 H), 7.34 (t, J=8.02Hz, 2 H), 7.14 (t, J=8.7 Hz, 2 H), 5.00 (d, J=9.9 Hz, 1 H), 4.54 (d,J=6.1 Hz, 2 H), 4.04-3.82 (m, 3 H), 3.55-3.43 (m, 4 H), 3.30-3.22 (m, 4H), 2.87 (s, 3 H), 1.21 (t, J=7.14 Hz, 3 H).

MS m/z 404 (M+H)⁺.

EXAMPLE 7B

Step 1:N-(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)-1-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

4-fluorobenzyl2-(1,2-dimethylpiperazin-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,obtained during the preparation of the compound in example 7 step 4, wasdissolved in THF/NaOH 2N (1:1) followed by the addition of iPrSO₂Cl (4eq). After being stirred at room temperature overnight, further additionof iPrSO₂Cl (2.4 eq) and NaOH 2N (2.4 eq) were made to complete thereaction. After 3 hours NaOH 2N (10 eq) was added and the reactionmixture was stirred for 10 minutes at room temperature. The titleproduct was isolated by preparative HPLC (Column C18, gradient ofCH₃CN/H₂O+0.01% TFA).

¹H NMR (DMSOd₆+TFA, 300K, 300 MHz) δ 9.48 (bt, J=6.5 Hz, 1H), 7.39-7.35(m, 2H), 7.7.22-7.12 (m, 2H), 4.96 (d, J=8.4 Hz, 1H), 4.57 (d, J=6.3 Hz,2H), 4.23 (d, J=14.4 Hz, 1H), 3.96 (d, J=10.8 Hz, 1H), 3.76 (d, J=10.2Hz, 1H), 3.53 (s, 3H), 3.50-3.35 (m, 3H), 3.23-3.15 (m, 1H), 2.87 (s,3H), 1.25 (d, J=6.9 Hz, 6H).

MS: m/z 482 (M+H)⁺.

EXAMPLE 8N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Methyl5-(benzoyloxy)-1-methyl-6-oxo-2-piperidin-2-yl-1,6-dihydropyrimidine-4-carboxylate(prepared from 1-(benzyloxycarbonyl)piperidine-2-carboxylic acid byprocedures similar to those set forth in Examples 1 or 2 in combinationwith a deprotection step) was suspended in THF and treated with 3 eq. oftriethylamine and 3 eq. of methyl iodide at 40° C. After stirring for 5h, THF was evaporated and residue poured into EtOAc and washed withbrine. Organic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure. The oily residue was taken into EtOAc and treated with3 eq. of 4-fluorobenzylamine at 90° C. for 0.5 h. The title product wasisolated as its trifluoroacetic salt by preparative RP-HPLC (C18, 5 μM,acetonitrile/water containing 0.1% TFA as eluant).

¹H NMR (DMSO-d₆, 400 MHz) δ 12.28 (bs, 1 H), 9.50 (bt, 1 H), 9.31 (bs, 1H), 7.37 (dd, J=5.6 Hz, 8.4 Hz, 2 H), 7.18 (t, J=8.8 Hz, 2 H), 4.8-4.6(m, 1 H), 4.57 (d, J=6.4 Hz, 2 H), 3.70-3.60 (m, 1 H), 3.50 (s, 3 H),3.4-3.3 (m, 1 H), 2.78 (bs, 3 H), 2.4-2.3 (m, 1 H), 1.92-1.46 (m, 5 H).

MS m/z 375 (M+H)⁺.

EXAMPLE 92-(1-Acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl5-(benzoyloxy)-1-methyl-6-oxo-2-pyrrolidin-2-yl-1,6-dihydropyrimidine-4-carboxylate

Methyl-5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylatewas treated with TFA:CH₂Cl₂ (3:7) at 0° C. The solution was warmed toroom temperature and the progress of the reaction was monitored by MSanalysis. After 1 h the reaction was complete and the solvent wasremoved under reduced pressure using a rotatory evaporator. The titleproduct was precipitated with Et₂O and collected by filtration.

¹H-NMR (CDCl₃, 400 MHz) δ 8.17 (d, J=7.4 Hz, 2 H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 2 H), 5.45 (dd, J=7.6, 6.7 Hz, 1 H), 3.82 (s, 3H), 3.66 (s, 3 H), 3.61 (t, J=7.0 Hz, 2 H), 2.78-2.69 (m, 1 H),2.40-2.00 (m, 3 H).

MS m/z 358 (M+H)⁺.

Step 2:2-(1-Acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

To a stirred solution of the product of Step 1 (1.0 eq.) in CHCl₃,triethylamine (3.0 eq.) was added followed by the addition of acetylchloride (1.5 eq.). The reaction was stirred at room temperature untilthe starting material was consumed as determined by MS analysis. Thereaction mixture was concentrated and the crude product was useddirectly in the subsequent step without further purification.

A solution of the crude product from above (1.0 eq.) in NMP was treatedwith 4-fluorobenzylamine (2.0 eq.). The solution was stirred at refluxuntil the reactants were consumed as determined by MS analysis. Thetitle compound was obtained by RP-HPLC purification (C₁₈, eluting withwater and acetonitrile containing 0.1% trifluoroacetic acid) as a 4:1mixture of rotamers by NMR.

¹H-NMR (DMSO-d₆, 400 MHz) δ 12.11 (bs, 1 H), 8.49 (t, J=6.2 Hz, 0.8 H),8.30 (t, J=6.2 Hz, 0.2 H), 7.4-7.3 (m, 2 H), 7.15 (t, J=8.8 Hz, 2 H),5.22 (dd, J=8.0, 3.2 Hz, 0.2 H), 5.02 (dd, J=8.0, 3.2 Hz, 0.8 H),4.60-4.47 (m, 2 H), 3.95-3.85 (m, 0.8 H), 3.80-3.70 (m, 0.2 H),3.59-3.57 (m, 0.8 H), 3.55 (s, 2.4 H), 3.52 (s, 0.6 H), 3.43-3.37 (m,0.2 H), 2.40-1.7 (m, 4 H), 2.5 (s, 2.4 H), 1.75 (s, 0.8 H).

MS m/z 389 (M+H)⁺.

EXAMPLE 102-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl2-(2,3-dihydro-1H-indol-2-yl)-1-methyl-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Benzyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidi-2-yl]indoline-1-carboxylatewas dissolved in EtOAc and hydrogenated at atmospheric pressure on 10%Pd/C overnight. The crude title product was obtained after filtrationand evaporation

Step 2: Methyl2-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-5-benzoyloxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

THF was added to the crude product of Step 1, followed by pyridine (2eq.) and PhCOCl (1 eq.). After being stirred at room temperatureovernight, the reaction mixture was evaporated to give the crude titleproduct.

Step 3:2-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The crude product of Step 2 was dissolved in MeOH and4-fluorobenzylamine (3.5 eq.) added. The solution was stirred at 60° C.over night. The title product was obtained by preparative RP-HPLC (C18,gradient of CH₃CN/H₂O+0.01% TFA).

¹H NMR (DMSO-d₆+TFA, 340 K, 400 MHz) δ 7.75-7.80 (m, 1 H), 7.45-6.97 (m,13H), 5.77 (dd, J=10, 3.6 Hz, 1 H), 4.35-4.50 (m, 2 H), 3.72 (dd, J=16,10 Hz, 1 H), 3.35 (s, 3 H), 3.16 (dd, J=16, 3.6 Hz, 1 H).

MS m/z 499 (M+H)⁺.

EXAMPLE 11N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl2-(1,2,3,4-tetrahydroquinolin-2-yl)-1-methyl-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Benzyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidi-2-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate(prepared from tetrahydroquinoline-2-carboxylic acid (Robl et al,Tetrahedron Letters 1995, 36: 1593) by protection of the nitrogen andfollowing procedures similar to those set forth in Examples 1 or 2 incombination with a deprotection step) was dissolved in EtOAc andhydrogenated at atmospheric pressure on 10% Pd/C at room temperatureovernight. The title product was obtained as the residue afterfiltration and evaporation of the organic solvent.

Step 2: Methyl5-benzoyloxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxylate

The residue of Step 1 was dissolved in dichloromethane. Pyridine,picolinoyl chloride hydrochloride and a catalytic amount of DMAP wereadded. A further addition of the reactants was made after two hours.After evaporation of the solvent, the residue was diluted with EtOAc,the organic phase washed with water, dried (Na₂SO₄) and evaporated toafford the title product.

Step 3:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide

The residue of Step 2 was dissolved in DMF and 4-fluorobenzylamine (3eq.) was added. The reaction mixture was stirred at 90° C. for 1 H. Thetitle compound was purified by preparative HPLC and isolated as itstrifluoroacetic salt (C18, gradient of CH₃CN/H₂O+0.01% TFA).

¹H-NMR (DMSO-d₆+TFA, 400 MHz, 340 K) δ 8.35 (d, J=4.2 Hz, 1 H), 7.81 (t,J=7.4 Hz, 1 H), 7.54 (bt, 1 H), 7.49 (d, J=7.7 Hz, 1 H), 7.37 (dd, J=5.2Hz, 7.0 Hz, 1H), 7.25-7.22 (m, 2 H), 7.17-7.09 (m, 3 H), 6.90 (t, J=7.3Hz, 1 H), 6.62 (t, J=7.3 Hz, 1 H), 6.43 (bs, 1 H), 5.74 (t, J=7.6 Hz, 1H), 4.42 (dd, J=6.4 Hz, 14.8 Hz, 1H), 4.32 (dd, J=6.4 Hz, 14.8 Hz, 1 H),3.65 (s, 3 H), 2.80-2.70 (m, 3 H), 1.85-1.75 (m, 1 H).

MS m/z 514 (M+H)⁺.

EXAMPLE 122-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-5-(benzoyloxy)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Methyl2-[(2S,4R)-1-tert-butyloxycarbonyl-4-(benzyloxy)pyrrolidin-2-yl]-5-(benzoyloxy)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate[obtained from N-Boc-O-benzyl-L-hydroxyproline using chemistry similarto those set forth in Examples 1 or 2; the stereochemistry of productsof Steps 1 to 3 is based on that of starting material] was dissolved indichloromethane (0.03 M), followed by addition of an excess of TFA. Themixture was stirred at room temperature for 1 hour. The solvent wasevaporated in vacuo. To the residue dissolved in pyridine, benzoicanhydride (2 eq.) was added. The mixture was stirred at room temperaturefor 5 hours. Pyridine was evaporated in vacuo and the residue dissolvedin EtOAc was washed with HCl (1M), saturated aqueous NaHCO₃ and brine,dried on Na₂SO₄, filtered and evaporated in vacuo to give the titleproduct as a yellow solid.

¹H NMR (DMSO-d₆, 400 MHz, 330 K) δ 8.07 (d, J=7.6 Hz, 2 H), 7.77 (t,J=7.3 Hz, H), 7.62 (t, J=7.74 Hz, 2 H), 7.52-7.49 (m, 5 H), 7.33-7.30(m, 5 H), 5.47 (bt, 1 H), 4.53 (d, J=12.1 Hz, 1 H), 4.44 (d, J=12.0 Hz,1 H), 4.36 (bs, 1 H), 3.87-3.84 (m, 1 H), 3.76 (s, 3 H), 3.73 (s, 3 H),3.57 (d, J=11.2 Hz, 1 H) 2.70 (t, J=12.2 Hz, 1 H), 2.31-2.28 (m, 1 H).

Step 2:2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The compound of Step 1 was dissolved in methanol and 4-fluorobenzylamine(5 eq.) was added. The mixture was refluxed overnight. After cooling,the reaction mixture was filtered and washed with ethyl ether to obtainthe title product as a white solid.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 12.15 (s, 1 H), 9.00 (br t, 1 H),7.48 (d, J=7.6 Hz, 2 H) 7.41-7.20 (m, 10 H), 7.12 (t, J=8.8 Hz, 2 H),5.27 (t, J=8 Hz, 1 H), 4.63 (dd, J=14.9, 7.3 Hz, 1 H), 4.56-4.38 (m, 2H), 4.26 (bs, 1 H) 4.25 (d, J=11.4 Hz, 2 H) 3.68 (s, 3 H), 3.52 (d,J=11.2 Hz, 1 H), 2.66-2.63 (m, 1 H), 2.26-2.20 (m, 1 H).

MS m/z 557 (M+H)⁺.

Step 3:2-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The title compound of Step 2 was dissolved in AcOH and 10% Pd/C (10%weight) was added. The mixture was stirred under H₂ at atmosphereovernight. Pd/C was filtered, AcOH evaporated in vacuo, and theresulting title compound was washed with methanol.

¹H NMR (DMSO-d₆, 400 MHz) δ 12.1 (s, 1 H), 9 (bt, 1 H), 7.51-7.47 (m, 3H), 7.41-7.33 (m, 4 H) 7.11 (t, J=8.8 Hz, 2 H), 5.27 (t, J=8 Hz, 1 H),5.08 (d, J=3.2 Hz, 1 H), 4.63 (dd, J=14.8 Hz, 7.3 Hz, 1 H), 4.43-4.39(m, 2 H), 4.20 (d, J=7.4 Hz, 1 H), 3.67 (s, 3 H), 2.41-2.36 (m, 1 H),2.2-2.1 (m, 1 H).

MS m/z 467 (M+H)⁺.

EXAMPLE 13N⁴-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-N²-(pyridin-2-ylmethyl)-1,6-dihydropyrimidine-2,4-dicarboxamide

2-Ethyl 4-methyl5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxylate(made by protection and alkylation of the starting material of Example4, Step 1 using procedures similar to those set forth in Examples 1 or2) was dissolved in DMF, 4-fluorobenzylamine (3.1 eq.) was added and themixture was stirred at 90° C. overnight. After concentration of thesolvent, the residue was taken into EtOAc, washed with 1 N HCl, driedover Na₂SO₄ and evaporated to obtain crudeN-(4-fluorobenzyl)-2-ethoxycarbonyl-1-methyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide.To this crude product was added 2-picolylamine (8 eq.), and the reactionwas stirred at 90° C. overnight. The title product was obtained as itstrifluoroacetic salt by preparative RP-HPLC purification (C18 gradientof CH₃CN/H₂O+0.01% TFA).

¹H NMR (DMSO-d₆, 300K, 400 MHz) δ 12.70 (bs, 1 H), 9.75-9.65 (m, 2 H),8.56 (d, J=4.4 Hz, 1 H), 7.90-7.80 (m, 1 H), 7.44 (d, J=8.0 Hz, 1 H),7.40-7.35 (m, 3 H), 7.17 (t, J=9.2, 2 H), 4.60 (d, J=6.0 Hz, 2 H), 4.54(d, J=6.0 Hz, 2 H), 3.67 (s, 3 H).

MS m/z 412 (M+H)⁺.

EXAMPLE 142-[2-(4-benzoylpiperazin-1-yl)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1:2-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Methyl2-(2,2-dimethoxyethyl)-5-benzoyloxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate(1.0 eq.) (prepared from 3,3-dimethoxypropionitrile by procedure similarto those set forth in Examples 1 or 2) in dry MeOH was treated with4-fluorobenzyl amine (2.5 eq.) at reflux for 2 hours. Solvent wasremoved in vacuo and residue triturated with Et₂O to obtain the titleproduct.

¹H NMR (DMSO-d₆, 300K, 400 MHz) δ: 9.80 (br s, 1H), 7.41-7.38 (m, 2H),7.15 (t, J=8.7 Hz, 2H), 5.04 (br s, 1H), 4.47 (d, J=6.2 Hz, 2H), 3.46(s, 3H), 3.28 (s, 6 H), 3.01 (d, J=5.5 Hz, 2 H).

MS: m/z 366 (M−H)+

Step 2:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(2-oxoethyl)-1,6-dihydropyrimidine-4-carboxamide

The product of Step 1 was treated with a mixture HCl 1N/THF for 1 hourat 40° C. Organics were removed in vacuo and residue extracted in DCM,dried over Na₂SO₄ and concentrated to give the title compound as a foamwhich was immediately reacted in the following reductive amination.

MS: m/z 320 (M+H)+.

Step 3:2-[2-(4-benzoylpiperazin-1-yl)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

The product of Step 2 was dissolved in MeOH and treated with sodiumacetate (1.6 eq.), 1-benzoylpiperazine (2 eq.), and sodiumcyanoborohydride (1.43 eq.). The mixture was left stirring at roomtemperature for 1 hour. The reaction mixture was concentrated and thetitle compound was obtained by RP-HPLC purification (C₁₈, eluting withwater and acetonitrile containing 0.1% TFA).

¹H NMR (CDCl₃+TFA, 273 K, 600 MHz) δ: 10.431 (br s, 1H), 8.38 (t, J=5.7Hz, 1H), 7.61 (t, J=6.4 Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.41 (d, J=7.4Hz, 2H), 7.28 (2 H, overlapped by CHCl₃), 7.07 (t, J=8.5 Hz, 2H), 4.97(d, J=14 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.10 (d, J=14 Hz, 1H), 3.93(d, J=11.9 Hz, 1H), 3.82-3.74 (m, 4H), 3.61 (s, 3H), 3.47 (t, J=12.6 Hz,1H), 3.41 (br s, 2H), 3.29-3-26 (m, 1H), 3.15-3.14 (m, 1H).

MS: m/z 494 (M+H)+.

EXAMPLE 15N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: Methyl1-allyl-5-[(2,2-dimethylpropanoyl)oxy]-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Methyl5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-1,6-dihydropyrimidine-4-carboxylate(see Example 4, Step 3) was dissolved in THF, then allyl bromide (2 eq.)and Cs₂CO₃ (2 eq.) were added. The reaction mixture was refluxed for 2H, then evaporated. The residue was diluted with EtOAc, washed with 1NHCl, dried (Na₂SO₄) and the solvent evaporated. The product was purifiedby flash chromatography on silica gel eluting with a gradient ofpetroleum ether/EtOAc.

¹H-NMR (DMSO-d₆, 400 MHz, 300K) δ 8.47 (s, 1H), 5.99-5.92 (m, 1H),5.25-5.14 (m, 2H), 4.58 (d, J=5.5 Hz, 2H), 3.82 (s, 3H), 1.28 (s, 9H).

Step 2:N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

2a. The compound of Step 1 was dissolved in dichloroethane and m-CPBAwas added (5 eq.). The reaction mixture was refluxed until the startingmaterial was completely consumed, then evaporated. MS m/z 311 (M+H)⁺.

2b. Crude material from step 2a was dissolved in MeOH and morpholine (6eq.) was added. The reaction mixture was refluxed for 3 H, thenevaporated. MS (EI+) m/z 398 (M+H)⁺.

2c. Crude material from step 2b was dissolved in DMF and4-fluorobenzylamine (3 eq.) was added. The reaction mixture was stirredat 90° C. for 3 h. The title compound was obtained as itstrifluoroacetate salt by RP-HPLC purification (gradient ofCH₃CN/H₂O+0.01% TFA).

¹H-NMR (DMSO-d₆+TFA, 400 MHz, 340K) δ 9.27 (bt, 1H), 7.94 (s, 1 H),7.40-7.36 (m, 2H), 7.15-7.11 (m, 2H), 4.48 (d, J=6.4 Hz, 2H), 4.30-4.36,(m, 1H), 4.09 (dd, J=13.6, 4.0 Hz, 1H), 3.91-3.86 (m, 5H), 3.34-3.30 (m,5H), 3.18 (dd, J=13.6 ,4.0 Hz, 1 H).

MS m/z 407 (M+H)⁺.

EXAMPLE 162-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: 1-Benzyl-2-methyl-(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate

1-benzyl-2-methyl(2S,4R)4-hydroxypyrrolidine-1,2 dicarboxylate indichloromethane was added dropwise to a solution, precooled to −78° C.,of N,N-diethylaminosulfur trifluoride (1.0 eq.) in dichloromethane. Thereaction was stirred while the temperature was allowed to increase to25° C. The solvent was concentrated under vacuum and the crude waspurified by flash chromatography (eluent: petroleum ether:EtOAc=1:1) togive the title compound.

¹H NMR (CDCl₃, 300 MHz, 300 K) δ 7.42-7.30 (m, 5H), 5.35-5.10 (m, 3H),4.65 (d, J=9.6 Hz, 0.5H), 4.57 (d, J=9.4 Hz, 0.5H), 3.99-3.62 (m, 2H),3.79 (s, 1.5H), 3.68 (s, 1.5H), 2.62-2.29 (m, 2H).

MS: m/z 282 (M+H)⁺.

Step 2: (4S)-1-[(Benzyloxy)carbonyl]-4-fluoro-L-proline

1-Benzyl-2-methyl-(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylatedissolved in methanol was treated with NaOH 1N (2 eq.) and the reactionmixture was stirred at 50° C. for 3 hours. After concentration of thesolvent, HCl 1N was added until pH=1 and the aqueous layer was extractedthree times with dichloromethane. The organic phase was washed withbrine, dried over Na₂SO₄ and filtered to give, after concentration,title compound.

¹HNMR (CDCl₃, 400 MHz, 300 K) δ 7.45-7.30 (m, 5H), 5.33-5.18 (m, 3H),4.70-4.60 (bm, 1H), 4.00-3.65 (m, 2H), 2.85-2.25 (m, 2H).

MS: m/z 268 (M+H)⁺.

Step 3: Benzyl-(2S,4S)-2-aminocarbonyl-4-fluoropyrrolidine-1-carboxylate

A stirred solution of (4S)-1-[(Benzyloxy)carbonyl]-4-fluoro-L-proline indioxane was treated with pyridine (0.7 eq.) and Boc₂O (1.3 eq.), thenammonium bicarbonate (1.26 eq.) was added and the mixture was stirred atroom temperature for 15 hours. Dioxane was concentrated and the residuewas taken up in ethyl acetate, washed with 1 N HCl and brine, dried overNa₂SO₄ to give, after filtration and concentration, title compound.

¹H NMR (DMSO-d₆, 400 MHz, 340 K) δ 7.40-7.28 (m, 5H), 5.25 (dt,J_(H-F)=53.6 Hz, J=4.5 Hz, 1H), 5.13-5.06 (m, 2H), 4.28 (d, J=9.6 Hz,1H), 3.80-3.63 (m, 2H), 2.45-2.21 (m, 2H).

MS: m/z 267 (M+H)⁺.

Step 4: Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate

Benzyl-(2S,4S)-2-aminocarbonyl-4-fluoropyrrolidine-1-carboxylate indichloromethane was treated at 0° C. with Et₃N (2.1 eq.) andtrifluoroacetic anhydride was added dropwise.

The reaction mixture was stirred at 0° C. for 0.5 hour and 10 minutes atroom temperature. Then, it was diluted with dichloromethane, washed withHCl 1N and brine, dried over Na₂SO₄ and filtered to give, afterconcentration, title compound.

¹H NMR (DMSO-d₆, 400 MHz, 340 K) δ 7.42-7.30 (m, 5H), 5.40 (dbt,J_(H-F)=52.3 Hz, 1H), 5.20 (d, J=12.7 Hz, 1H), 5.16 (d, J=12.7 Hz, 1H),4.94 (d, J=8.4 Hz, 1H), 3.68-3.56 (m, 2H), 2.63-2.41(m, 2H).

MS: m/z 249 (M+H)⁺.

Step 5:Benzyl-(2S,4S)-2-[amino(hydroxyimino)methyl]-4-fluoropyrrolidine-1-carboxylate

Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate dissolved inabsolute ethanol was treated with triethyl amine (1.5 eq.) andhydroxylamine hydrochloride (1.3 eq.).

The reaction mixture was stirred at 50° C. for 3 hours and then thesolvent was removed under reduced pressure. The residue was partitionedbetween water and dichloromethane and the aqueous layer was extractedwith dichloromethane three times. The organic phase was dried overNa₂SO₄ and filtered. The solid obtained by concentration was thenrecrystallized from MeOH to give title compound.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 9.10 (bs, 1H), 7.40-7.25 (m, 5H),5.35-5.15 (m, 3H), 5.07 (m, 2H), 4.43 (d, J=9.1 Hz, 1H), 3.72-3.56 (m,2H), 2.45-2.20 (m, 2H).

MS: m/z 282 (M+H)⁺.

Step 6:Dimethyl-2-{[(amino-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioate

Benzyl-(2S,4S)-2-[amino(hydroxyimino)methyl]-4-fluoropyrrolidine-1-carboxylatein chloroform was treated with dimethylacetylene dicarboxylate for 3hours at 60° C. The chloroform was then concentrated to give the titlecompound as a 8:2 mixture of isomers.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 7.45-7.25 (m, 5H), 6.51 (bs, 1.6 H),6.14 (bs, 0.4 H), 5.64 (s, 0.8H), 5.61 (s, 0.2 H), 5.30 (dt,J_(H-F)=53.9 Hz, J=4.6 Hz, 1H), 5.15-5.04 (m, 2H), 4.51 (t, J=8.8 Hz,0.8H), 4.44 (bt, 0.4H), 3.85-3.48 (m, 8H), 2.67-2.23 (m, 2H).

MS: m/z 424 (M+H)⁺.

Step 7:Methyl-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-5,6-dihydroxypyrimidine-4-carboxylate

Dimethyl-2-{[(amino-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioatewas refluxed for 6 hours in ortho-xylene.

The reaction mixture was then cooled down to room temperature andpetroleum ether was added. A light brown solid precipitated to giveafter filtration title compound, that was not purified furthermore, butused as such in the following reaction.

Step 8:Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate

Methyl-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-5,6-dihydroxypyrimidine-4-carboxylatein pyridine was treated with benzoic anhydride (1.3 eq.) and thereaction mixture was stirred at room temperature overnight.

Pyridine was concentrated and the residue was taken up in ethyl acetateand washed with HCl 1N and brine. The organic phase was dried overNa₂SO₄ and filtered to give after concentration a crude that waspurified by flash chromatography, (eluent: petroleum ether:ethylacetate=1:1) to give title compound.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 13.50 (bs, 1H), 8.09 (d, J=7.7 Hz,2H), 7.80 (t, J=7.35 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 7.45-7.15 (m, 5H),5.36 (dbt, J_(H-F)=54 Hz, 1H), 5.14 (m, 2H), 5.02-4.93 (m, 1H),3.95-3.60 (m, 2H), 3.76 (s, 3H), 2.80-2.36 (m, 2H).

MS: m/z 496 (M+H)⁺.

Step 9:Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate,dissolved in dry dioxane, was added to a suspension of lithium hydride(1.2 eq.) in dry dioxane. The reaction mixture was stirred at 38° C. for45 minutes and then cooled down to room temperature. Dimethyl sulfate(1.3 eq.) was added and the mixture was heated to 58° C. and stirred atthis temperature for 3 hours. The reaction mixture was then cooled downand glacial acetic acid (0.2 eq.) was added, followed by water and ethylacetate. The aqueous layer was separated and extracted with ethylacetate; the organic phase was dried over Na₂SO₄ and filtered to give,after concentration, a crude that was purified by flash chromatography(eluent petroleum ether:ethyl acetate from 4:6 to 2:8) to give the titlecompound as a 4.6:5.4 mixture of rotamers by NMR.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 8.08 (d, J=7.5 Hz, 2H), 7.79 (t,J=7.3 Hz, 1H), 7.63 (t, J=7.5 Hz, 2H), 7.37-7.11 (m, 5H), 5.48-5.38 (m,2H), 5.20 (d, J=12.8 Hz, 0.46H), 5.12 (d, J=11.8 Hz, 0.54H), 5.10 (d,J=12.5 Hz, 0.54H), 4.92 (d, J=12.8 Hz, 0.46H), 4.00-3.75 (m, 2H), 3.72(s, 3H), 3.59 (s, 1.6H), 3.52 (s, 1.4H), 2.90-2.65 (m, 2H).

MS: m/z 510 (M+H)⁺.

Step 10:Methyl-2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylate.

Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,dissolved in ethyl acetate was treated with Pd/C 10% (10% w/w) andacetic anhydride (1 eq.) and submitted under H₂ atmosphere at roomtemperature. The reaction mixture was stirred at room temperature for 18hours and then the suspension was filtered over celite to give the titlecompound as a 7:3 mixture of rotamers by NMR.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 8.07 (m, 2H), 7.78 (m, 1H), 7.62 (m,2H), 5.75-5.26 (m, 2H), 4.13-3.60 (m, 2H), 3.72 (s, 3H), 3.59 (s, 3H),2.79-2.36 (m, 2H), 2.03 (s, 2.1H), 1.87 (s, 0.9H).

MS: m/z 418 (M+H)⁺.

Step 11:2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.

Methyl-2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylatewas dissolved in MeOH (0.12 N) and treated with 4-F-benzylamine (3 eq.)in a sealed tube. The reaction mixture was stirred at 65° C. for 18hours, then it was cooled down. The solvent was evaporated and theresidue was washed with ethyl ether several times to obtain a solid thatwas recrystallized from ethanol and washed again with ethyl ether togive the title compound as a 7.3:2.7 mixture of rotamers by NMR.

¹H NMR (DMSO-d₆, 500 MHz, 300 K) δ 12.01 (bs, 1H), 8.52 (t, J=6.3 Hz,0.7H), 8.34 (t, J=6.3 Hz, 0.3H), 7.34-7.29 (m, 2H), 7.18-7.12 (m, 2H),5.39 (dbt, J_(H-F)=54.3 Hz, 0.7H), 5.29 (dt, J_(H-F)=54.2 Hz, J=4.4 Hz,0.3 H), 5.38 (d, J=8.9 Hz, 0.3H), 5.18 (dd, J=9.2 and 1.6 Hz, 0.7H),4.55-4.47 (m, 2H), 4.20-3.78 (m, 2H), 3.51 (s, 2.1H), 3.50 (s, 0.9H),2.75-2.54 (m, 1H), 2.47-2.27 (m, 1H), 2.00 (s, 2.1H), 1.81 (s, 0.9H).

MS: m/z 407 (M+H)⁺.

EXAMPLE 172-{(2S,4R)-1-[(dimethylamino)(oxo)acetyl]-4-methoxypyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: (4R)-1-[(Benzyloxy)carbonyl]-4-methoxy-L-proline

Synthesized following the procedure reported on Journal of MedicinalChemistry 1988, 31, 875-885.

Step 2: Benzyl-(2S,4R)-2-cyano-4-methoxypyrrolidine-1-carboxylate

To compound (4R)-1-[(Benzyloxy)carbonyl]-4-methoxy-L-proline dissolvedin dioxane, Boc anhydride (1.3 eq), NH₄HCO₃ (1.26 eq.) and pyridine wereadded. The mixture was stirred overnight at room temperature. Dioxanewas removed in vacuo and the residue, dissolved in ethyl acetate, waswashed with HCl 1N, saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄, filtered and concentrated in vacuo to get the primary amide. Thecrude product was dissolved in dichloromethane and triethylamine (2.1eq.) was added. Them mixture was cooled down to 0° C. andtrifluoroacetic anhydride (1.1 eq.) was added. After 1 hour thedichloromethane solution was diluted and washed with HCl 1N, saturatedaqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated invacuo. The compound was purified by flash chromatography on silica gel(eluent ethyl acetate:petroleum ether=20%:80%) as a 4:6 mixture ofrotamers by NMR.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 7.45-7.3 (m, 5H), 5.20 (d, J=12 Hz,0.4H), 5.14 (s, 1.2H), 5.12 (d, J=12 Hz, 0.4H), 4.75 (t, J=7 Hz, 0.4H),4.64 (t, J=7.8 Hz, 0.6H), 4.02 (bs, 1H), 3.6-3.45 (m, 2H), 3.21 (s, 3H),2.45-2.40 (partially under DMSO) (in, 1H), 2.40-2.25 (m, 1H).

Step 3:Benzyl-(2S,4R)-2-[amino(hydroxyimino)methyl]-4methoxypyrrolidine-1-carboxylate

To benzyl-(2S,4R)-2-cyano-4-methoxypyrrolidine-1-carboxylate, dissolvedin ethanol (0.4 M), hydroxylamine hydrochloride (1.3 eq.) andtriethylamine (1.5 eq.) were added. The mixture was stirred at 40° C.for 4 hours then at room temperature overnight. The mixture wasconcentrated in vacuo and the residue dissolved in ethyl acetate washedwith brine, dried over Na₂SO₄, filtered and concentrated to give titlecompound.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 9.05 (bs, 1H), 7.45-7.25 (m, 5H), 5.4(bs, 2H), 5.10 (d, J=13 Hz, 1H), 5.03 (d, J=13 Hz, 1H), 4.26 (t, J=7.4Hz, 1H), 3.97 (bs, 1H), 3.63-3.45 (m, 2H), 3.22 (s, 3H) 2.3-2.03 (m,2H).

Step 4:Dimethyl-2-{[(amino-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioate

Tobenzyl-(2S,4R)-2-[amino(hydroxyimino)methyl]-4methoxypyrrolidine-1-carboxylate,dissolved in chloroform, dimethyl acetylendicarboxylate (1.1 eq.) wasadded. The mixture was refluxed for 1 hour and left stirring at 40° C.overnight. The chloroform was removed in vacuo and the crude productpurified by flash chromatography on silica gel (eluent ethylacetate:petroleum ether=40:60). Two isomers were present in ratio 7:3.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 7.40-7.23 (m, 5H), 6.7-6.55 (2bs, 1.4H), 6.35-6.2 (bs, 0.6H), 5.61 (s, 0.7H), 5.59 (s, 0.3H), 5.10 (d, J=13Hz, 0.7H), 5.08 (s, 0.6H), 5.02 (d, J=13 Hz, 0.7H), 4.30-4.20 (m, 1H),3.97 (bs, 1H), 3.78 (s, 2.1H), 3.73 (s, 0.9H), 3.62 (s, 0.9H), 3.59 (s,2.1H), 3.65-3.50 (m, 2H), 3.22 (s, 3H), 2.37-2.23 (m, 1H), 2.10-1.95 (m,1H).

Step 5: Methyl5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate

Dimethyl-2-{[(amino-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioatewere dissolved in xylene and the solution stirred at 150° C. for 3 hoursand at room temperature overnight. Xylene was concentrated in vacuo. Tothe crude compound, dissolved in pyridine, benzoic anhydride (1.3 eq.)was added and the reaction mixture was stirred at room temperatureovernight. The solution was concentrated in vacuo and the crudedissolved in ethyl acetate washed with 1 N HCl, saturated aqueous NaHCO₃and brine, dried on Na₂SO₄, filtered and evaporated in vacuo. The crudeproduct was purified by flash chromatography on silica gel (eluent ethylacetate:petroleum ether=10:90) and showed a 1:1 mixture of rotamers byNMR.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 13.5 (s, 1H), 8.09 (t, J=7.0 Hz, 2H),7.82-7.75 (m, 1H), 7.66-7.61 (m, 2H), 7.40-7.25 (m, 4 H), 7.12-7.06 (m,1H), 5.10 (s, 1H), 5.09 (d, J=12.5 Hz, 0.5H), 4.88 (d, J=12.5 Hz, 0.5H),4.66 (dd, J=16.2 and 8.0 Hz, 1H), 4.10-4.00 (m, 1H), 3.74 (s, 3H),3.75-3.60 (m, 2H), 3.25 (s, 3H), 2.45-2.40 (partially under DMSO) (m,1H), 2.13-2.03 (m, 1H).

Step 6:Methyl-5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

To methyl5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate,dissolved in dioxane, LiH (1.4 eq.) was added and the reaction mixturestirred at 38° C. for 40 minutes. The temperature was raised to 60° C.and dimethyl sulphate (1.3 eq.) was added dropwise. After two hours thereaction mixture was cooled down to 0° C. and HCl 1 N was added toquench the reaction. The reaction mixture was extracted with ethylacetate and the organic phase washed with HCl 1N, saturated aqueousNaHCO₃ and brine, dried on Na₂SO₄, filtered and concentrated in vacuo.The desired product was isolated by flash chromatography on silica gel(eluent ethyl acetate:petroleum ether=30:70) as a 1:1 mixture ofrotamers by NMR:

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 8.08 (t, J=6.8, 2H), 7.82-7.75 (m,1H), 7.66-7.61 (m, 2H), 7.38-7.22 (m, 4H), 7.08-7.02 (m, 1H), 5.18-5.12(m, 1H), 5.13 (d, J=13.1 Hz, 0.5H), 5.07 (d, J=13.1 Hz, 0.5H), 5.06 (d,J=12.4 Hz, 0.5H), 4.84 (d, J=12.4 Hz, 0.5H), 4.08-4.17 (m, 1H), 3.73 (s,3H), 3.75-3.55 (m, 2H), 3.65 (s, 1.5H), 3.44 (s, 1.5H), 3.26 (s, 3H),2.62-2.52 (partially under DMSO) (m, 1H), 2.30-2.15 (m, 1H).

MS: m/z 522 (M+H)⁺

Step 7:Benzyl-(2S,4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methoxypyrrolidine-1-carboxylate

Tomethyl-5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,dissolved in methanol, 4-F-benzylamine (3 eq.) was added. The reactionmixture was stirred at reflux overnight. Methanol was removed in vacuoand the residue triturated with ethyl ether to give the title product asa 4:6 mixture of rotamers by NMR:

¹H NMR (DMSO-d₆+TFA, 400 MHz, 300 K) δ 14.0 (bs, 1H), 8.92 (t, J=6.4 Hz,0.4H), 8.73 (t, J=5.9 Hz, 0.6H), 7.35-7.25 (m, 4H), 7.20-7.05 (m, 4H),6.93 (d, J=7.5 Hz, 1H), 5.094.95 (m, 1H), 5.09 (d, J=12.3 Hz, 0.6H),4.75 (d, J=12.3 Hz, 0.6H), 5.05 (d, J=13 Hz, 0.4H), 4.98 (d, J=13 Hz,0.4H), 4.52-4.43 (m, 2H), 4.12-4.06 (bm, 0.4H), 4.06-4.02 (bm, 0.6H),3.87 (dd, J=11.5 and 4.5 Hz, 0.4H), 3.84 (dd, J=12 and 2.7 Hz, 0.6H),3.65-3.55 (m, 1H), 3.59 (s, 1.2H), 3.41 (s, 1.8H), 3.25 (s, 3H),2.45-2.40 (partially under DMSO) (m, 1H), 2.30-2.15 (m, 1H).

MS: m/z 511 (M+H)⁺

Step 8:N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-methoxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Benzyl-(2S,4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methoxypyrrolidine-1-carboxylatewas dissolved in methanol and Pd/C 10% wt (14% w/w) was added. Themixture was stirred under H₂ atmosphere at room temperature. After 2hours the reaction mixture was filtered and methanol was removed invacuo to give title compound.

¹H NMR (DMSO-d₆+TFA, 400 MHz, 300 K) δ 12.58 (bs, 1H), 10.16 (bs, 1H),9.74 (t, J=6.3 Hz, 1H), 8.90 (bs, 1H), 7.36 (dd, J=8.5 and 5.7 Hz, 2H),7,19 (t, J=8.8 Hz, 2H), 5.01 (bs, 1H), 4.50-4.60 (m, 2H), 4.19 (bs, 1H),3.55-3.45 (m, 1H), 3.47 (s, 3H), 3.45-3.35 (m, 1H), 3.32 (s, 3H), 2.74(dd, J=13.9 and 7.5 Hz, 1H), 2.17-2.10 (m, 1H).

MS: m/z 377 (M+H)⁺

Step 9:2-{(2S,4R)-1-[(dimethylamino)(oxo)acetyl]-4-methoxypyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

ToN-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-methoxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,triethylamine (1 eq.) was added. The reaction mixture was cooled down to0° C. and methyl chlorooxoacetate (3 eq.) was added. After 1 hour thereaction mixture was concentrated and a big excess of dimethylamine 2Min THF (30 eq.) was added The reaction mixture was concentrated and thedesired compound was isolated by HPLC purification (Waters, SymmetryC₁₈, 5 um, 19×50 mm eluting with water and acetonitrile containing 0.1%trifluoroacetic acid) as a 2:8 mixture of rotamers by NMR:

¹H NMR (DMSO-d₆, 400 MHz, 340 K) δ 11.9 (bs, 1H), 8.99 (bs, 0.8H), 8.85(bs, 0.2H), 7.40-7.30 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 5.21 (t, J=7.5Hz, 1H), 4.54 (dd, J=14.9 and 6.7 Hz, 1H), 4.45 (dd, J=14.9 and 6.4 Hz,1H), 4.10 (bs, 1H), 3.91 (dd, J=11.6 and 4.6 Hz, 0.2H), 3.79 (dd, J=11.2and 4.4 Hz, 0.8H), 3.60-3.50 (m, 1H), 3.58 (s, 2.4H), 3.48 (s, 0.6H),3.29 (s, 0.6H), 3.27 (s, 2.4H), 2.87 (s, 2.4H), 2.81 (s, 2.4H), 2.64 (s,0.6H), 2.57 (s, 0.6H), 2.70-2.50 (m, 1H), 2.30-2.20 (m, 0.8H), 2.20-2.10(m, 0.2H).

MS: m/z 476 (M+H)⁺

EXAMPLE 18N¹-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N²,N²-dimethylethanediamide(11)

Step 1: 2-Amino-2-methylpropanenitrile

Organic Synthesis Coll. Vol. II pg 29

Acetone cyanohydrin was diluted with MeOH (approx. 3 mmol/mL). Thesolution was cooled and saturated with ammonia gas, and the reactionmixture was allowed to stand for one day. The excess of ammonia andmethyl alcohol were evaporated by rotary evaporation. Residue consistedin the title product.

Step 2: Benzyl 1-cyano-1-methylethylcarbamate

To a suspension of 2-amino-2-methylpropanenitrile in water an equimolaramount of Na₂CO₃ and a slight excess (1.1 eq) of benzylchloroformatewere added, with an external cooling. Reaction mixture was stirred o/nat room temperature, extracted in EtOAc and the organic phase was washedwith NaHCO₃ss, dried (Na₂SO₄), filtered and concentrated. Product wasobtained as a white solid.

¹H-NMR (CDCl₃) δ 7.48-7.33 (bs, 5 H), 5.15 (s, 2 H), 4.98 (bs, 1 H),1.68 (s, 6 H);

¹³C-NMR (CDCl₃) δ 153.33, 13.81, 127.81, 127.63, 127.55, 120.64, 66.56,46.19, 26.67; MS (M+1) m/z 219.

Step 3: Benzyl 2-amino-2-(hydroxyimino)-1,1-dimethylethylcarbamate

Hydroxylamine hydrochloride in methanol was added to an equimolarstirred solution of potassium hydroxide in methanol. The mixture wasstirred for 15 min and the precipitated potassium chloride was removedby filtration. The filtrate was added to an equimolar amount of thenitrile and the solution stirred overnight at 40° C., then cooled toroom temperature and concentrated. The resulting residue was trituratedwith water and the white solid, after drying under vacuum, consistsmainly in the title product.

¹H-NMR (DMSO) δ 9.12 (bs, 1 H), 7.48 (bs, 5 H), 7.08 (bs, 1 H), 5.33(bs, 2 H), 4.98 (s, 2 H), 1.39 (s, 6 H); MS (M+1) m/z 252.

Step 4: Methyl2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate.

Benzyl 2-amino-2-(hydroxyimino)-1,1-dimethylethylcarbamate was suspendedin chloroform and treated with 1.2 eq of dimethylacetylenedicarboxylateand reaction was refluxed overnight. After cooling at room temperature,volatiles were evaporated and the residue was taken into xylene andheated at 145° C. for 48 h. The reaction mixture was stirred at roomtemperature overnight to allow the precipitation of the product (5) as alight brown solid. This solid was collected by filtration and washedwith diethyl ether.

¹H-NMR (DMSO) δ 12.54 (s, 1 H), 10.21 (s, 1 H), 7.44 (bs, 1 H), 7.30(bs, 5 H), 4.95 (s, 2 H), 3.80 (s, 3 H), 1.47 (s, 6 H); MS (M+1) m/z362.

Step 5: Methyl5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-6-hydroxypyrimidine-4-carboxylate.

To a stirred solution of methyl2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylatein pyridine, 1.1 eq of benzoic anhydride were added and stirringprolonged at room temperature over night. Pyridine was evaporated andresidue was taken in ethyl acetate and washed with 1 N HCl and brine.Organic layer was separated, dried (Na₂SO₄), filtered and concentratedby rotary evaporation and residue was purified by flash columnchromatography (SiO2, petroleum ether/ethyl acetate 60/40 v/v aseluant). Collection and evaporation of appropriate fractions affordedtitle product.

¹H-NMR (CDCl₃) δ 12.2 (bs, 1 H), 8.15 (d, J=7.4 Hz, 2 H), 7.65 (t, J=7.4Hz, 1 H), 7.50 (t, J=7.5 Hz, 2 H), 7.32 (bs, 5 H), 5.54 (bs, 1 H), 5.05(s, 2 H), 3.82 (s, 3 H), 1.67 (s, 6 H); MS (M+1) m/z 466.

Step 6: Methyl5-(benzoyloxy)-2-(1-{([(benzyloxy)carbonyl]amino}-1-methylethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

To a stirred solution of LiH (1.1 eq) in dioxane, methyl5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-6-hydroxypyrimidine-4-carboxylatewas added and the mixture was stirred at 38° C. for 45 min. Aftercooling down to room temperature, dimethylsulfate (1.3 eq) was added andreaction mixture was heated at 60° C. for 2 H. Mixture was then cooledto room temperature, dioxane evaporated and residue was purified byflash chromatography, eluting with 65/55 v/v petroleum ether/ethylacetate. Collection and evaporation of appropriate fractions affordedthe title product.

¹H-NMR (CDCl₃) δ 8.19 (d, J=7.3 Hz, 2 H), 7.65 (t, J=7.3 Hz, 1 H), 7.51(t, J=7.6 Hz, 2 H), 7.33 (bs, 5 H), 5.63 (bs, 1 H), 5.03 (s, 2 H), 3.80(s, 3 H), 3.63 (bs, 3 H), 1.72 (s, 6 H); MS (M+1) m/z 480.

Step 8: Benzyl1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethylcarbamate.

To a methanolic solution of methyl5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,p-fluoro benzylamine (3 eq) was added and mixture was refluxed overnight. After evaporation of methanol, residue was taken in EtOAc, washedwith 1N HCl and brine, dried (Na₂SO₄), filtered and evaporated to obtainthe title product.

¹H-NMR (CDCl₃) δ 11.9 (bs, 1 H), 7.79 (bt, 1 H), 7.35-7.29 (m, 7 H),7.07 (t, J=8.6 Hz, 2 H), 5.27 (bs, 1 H), 5.02 (bs, 2 H), 4.58 (d, J=6.2Hz, 2 H), 3.67 (s, 3 H), 1.70 (s, 6 H); MS (M+1) m/z 469.

Step 9:2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.

A methanolic solution of Benzyl1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethylcarbamatewas stirred over night under a hydrogen atmosphere in the presence ofcatalytic 10% Pd/C. Catalyst was then filtered off through celite, andthe filtrate was concentrated. Product was obtained after triturationwith ethyl ether.

¹H-NMR (DMSO) δ 12.31 (bs, 1 H), 9.68 (bt, J=6.6 Hz, 1 H), 8.60 (bs, 2H), 7.43 (dd, J=8.4 Hz, J=5.7 Hz, 2 H), 7.20 (t, J=8.8 Hz, 2 H), 4.54(d, J=6.6 Hz, 2 H), 3.56 (s, 3 H), 1.73 (s, 6 H); MS (M+1) m/z 335.

Step 10: Methyl{[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]amino}(oxo)acetate.

To a stirred mixture of2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(4) and triethyl amine (3 eq) in chloroform, methyl chlorooxoacetate(1.5 eq) was added with an external cooling. Finished the addition, theice bath was removed and the mixture was stirred at room temperature for3 H. Reaction mixture was then partitioned between chloroform and 1NHCl. Organic layer was separated, washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain title product.

¹H-NMR (DMSO) δ 12.2 (bs, 1 H), 9.47 (s, 1 H), 9.04 (t, J=6.3 Hz, 1 H),7.38 (dd, J=8.4 Hz, J=5.7 Hz, 2 H), 7.16 (t, J=8.8 Hz, 2 H), 4.50 (d,J=6.3 Hz, 2 H), 3.78 (s, 3 H), 3.45 (s, 3 H), 1.67 (s, 6 H); MS (M+1)m/z 421.

Step 11:N¹-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N²,N²-dimethylethanediamide(11).

Methyl{[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]amino}(oxo)acetatewas refluxed in an excess of 2 M solution of dimethylamine in THF for 2h. Reaction mixture was cooled to room temperature, evaporated andresidue was purified by RP HPLC (C₁₈, water/acetonitrile containing 0.1%of trifluoroacetic acid as eluant). Collection and lyophilization ofappropriate fractions afforded the title product.

¹H-NMR (DMSO) δ 12.19 (s, 1 H), 9.32 (s, 1 H), 9.06 (t, J=6.4 Hz, 1 H),7.40 (dd, J=8.5 Hz, J=5.7 Hz, 2 H), 7.18 (t, J=8.8 Hz, 2 H), 4.51 (d,J=6.4 Hz, 2 H), 3.55 (s, 3 H), 2.93 (s, 3 H), 2.87 (s, 3 H), 1.68 (s, 6H); ¹³C-NMR (DMSO) δ 168.23, 163.76, 163.09, 161.20 (d, J=96.4 Hz),158.46, 151.90, 145.49, 134.77, 129.40 (d, J=3.2 Hz), 124.29, 115.05 (d,J=8.5 Hz), 56.50, 41.51, 35.46, 33.42, 32.68, 26.85;

MS (M+1) m/z 434; MS (M+1) m/z 434.

EXAMPLE 19 Step 1:N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide

A solution of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid was treatedwith 1.9 equivalents of oxalyl chloride and a few drops of anhydrousN,N-dimethylformamide. After 1 H, mixture was concentrated, residue wastriturated with n-hexane and directly added to an equimolar solution of2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(described in step 9, example 18) in acetonitrile. Triethyl amine (3 eq)was added to the mixture and the reaction was stirred overnight at roomtemperature. Title product was isolated by prep RP HPLC (C18,acetonitrile/water containing 0.1% of trifluoroacetic acid as eluant).

¹H-NMR (DMSO) δ 12.2 (bs, 1 H), 9.84 (s, 1 H), 9.05 (t, J=6.5 Hz, 1 H),7.38 (dd, J=8.4 Hz, J=5.6 Hz, 2 H), 7.17 (t, J=8.8 Hz, 2 H), 4.50(d,J=6.5 Hz, 2 H), 2.56 (s, 3 H), 1.74 (s, 6 H), one methyl signal obscuredby water; MS (M+1) m/z 445.

EXAMPLE 202-{(2S)-1-[(dimethylamino)(oxo)acetyl]-4,4-difluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: 1-Benzyl-2-methyl-(2S)-4-oxopyrrolidine-1,2-dicarboxylate

A solution of dimethyl sulfoxide (2.1 eq) in dry dichioromethane wasadded dropwise to a stirred solution of oxalyl chloride (1.01 eq) in drydichloromethane (1.25 N) at −78° C. under N₂ atmosphere. After 15 min, asolution of the commercially available1-benzyl-2-methyl-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate in drydichloromethane was added slowly, and stirring was continued for 30 minat −78° C. After addition of triethylamine (5 eq), the mixture wasgradually warmed up to room temperature. The mixture was quenched withwater and aqueous layer was separated and extracted withdichloromethane. The extract was washed with brine and dried overNa₂SO₄. Concentration of the solvent in vacuo gave a residue, which waspurified by flash chromatography (ethyl acetate:petroleum ether=3:7) togive title product as a yellow oil.

¹H NMR (DMSO-d₆+TFA, 400 MHz, 330 K) δ 7.40-7.32 (m, 5H), 5.20-5.09 (m,2H), 4.79 (d, J=9.7 Hz, 1H), 3.95 (d, J=17.9 Hz, 1H), 3.78 (d, J=17.9Hz, 1H), 3.64 (s, 3H), 3.13 (dd, J=18.7 and 10.6, 1H), 2.62 (dd, J=18.7and 2.7 Hz, 1H).

MS: m/z 278 (M+H)⁺

Step 2: 1-Benzyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate

A solution of 1-benzyl-2-methyl-(2S)-4-oxopyrrolidine-1,2-dicarboxylatein dichloromethane was slowly added to a solution of diethylaminosulfurfluoride in dichloromethane precooled to −78° C. The reaction mixturewas warmed to room temperature and mixed with cold water. The organiclayer was separated, washed with water, dried over Na₂SO₄ and evaporatedto give title compound as a yellow oil.

¹H NMR (DMSO-d₆, 400 MHz, 330K) δ 7.40-7.32 (m, 5H), 5.16-5.12 (m, 2H),4.63 (br s, 1H), 3.96-3.80 (m, 2H), 3.65 (s, 3H), 3.15-2.86 (m, 1H),2.56-2.45 (partially under DMSO) (m, 1H).

¹⁹F NMR ¹H-¹⁹F dec (DMSO-d₆, 400 MHz, 330 K) δ −98.13 (d, J=223.7Hz)+−98.72 (d, J=223.6 Hz) (rotamer a), −101.38 (d, J=190.7 Hz)+−102.00(d, J=191.3 Hz) (rotamer b) (2F).

MS m/z 300 (M+H)⁺.

Step 3: 1-[(Benzyloxy)carbonyl]-4,4-difluoro-L-proline

A solution of 1-benzyl 2-methyl(2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate in methanol was refluxedwith 2N NaOH (2 eq) for 2 hours. Methanol was removed and pH adjusted to1 with 3 N HCl obtaining a suspension which was extracted several timeswith ethyl acetate. Combined organics were dried over Na₂SO₄ andevaporated to give title product as a dark brown oil.

¹H NMR (DMSO-d₆, 400 MHz, 330K) δ 12.96 (br s, 1H), 7.36-7.31 (m, 5H),5.11 (s, 2H), 4.50 (bs, 1H), 3.91-3.80 (m, 2H), 3.01-2.82 (m, 1H),2.56-2.41 (partially under DMSO) (m, 1H).

MS: m/z 284 (M−H)⁺.

Step 4:Benzyl-(2S)-2-aminocarbonyl-4,4-difluoropyrrolidine-1-carboxylate

To a stirred solution of 1-[(benzyloxy)carbonyl]-4,4-difluoro-L-proline,pyridine (0.6 eq.) and di-t-butyl dicarbonate (1.3 eq) in dioxane,ammonium bicarbonate (1.26 eq) was added and the mixture was stirred atroom temperature for 20 hours. Dioxane was concentrated and the residuedissolved in ethyl acetate and washed with HCl 1 N, saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated in vacuo toobtain a yellow oil.

Two sets of signals, two conformers (ratio 1:1) were present.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 7.56 (d, J=15.4 Hz, 1H), 7.39-7.34(m, 5H), 7.17 (d, J=19.3 Hz, 1H), 5.10-5.08 (m, 2H), 4.42 (dd, J=9.3 and4.7, 0.5 H), 4.34 (dd, J=9.2 and 4.6 Hz, 0.5 H), 3.92-3.73 (m, 2H),2.90-2.72 (m, 1H), 2.43-2.30 (m, 1H).

MS: m/z 285 (M+H)⁺.

Step 5: Benzyl-(2S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylate

A solution ofbenzyl-(2S)-2-aminocarbonyl-4,4-difluoropyrrolidine-1-carboxylate andtriethylamine (2.1 eq.) in dichloromethane was cooled to 0° C. andtrifluoroacetic anhydride (1.1 eq.) was added dropwise under nitrogen.Stirring was continued for 1 hour allowing the mixture to reach roomtemperature. Volatiles removed in vacuo and residue taken up in ethylacetate, washed with HCl 1N, brine and dried over Na₂SO₄. Evaporationgave title compound as brown oil.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 7.40-7.34 (m, 5H), 5.20-5.03 (m, 3H),3.99-3.72 (m, 2H), 3.06-2.69 (m, 2H).

Step 6:Benzyl-(2S)-2-[amino(hydroxyimino)methyl]-4,4-difluoropyrrolidine-1-carboxylate

A solution of benzyl-(2S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylate,hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) inethanol was refluxed under nitrogen for 5 hours. Mixture wasconcentrated and residues taken up in ethyl acetate and washed withwater and brine. Combined organics were dried over Na₂SO₄ and evaporatedto give title compound as a foam.

¹H NMR (DMSO-d₆, 300 MHz, 330 K) δ 9.12 (bs, 1H), 7.38-7.34 (m, 5H),5.36 (bs, 2H), 5.13 (d, J=14.4 Hz, 1H) +5.09 (d, J=14.4 Hz, 1H), 4.56(dd, J=8.6 and 4.9 Hz, 1H), 4.07-3.76 (m, 2H), 2.80-2.71 (m 1H),2.60-2.51 (partially under DMSO) (m, 1H).

MS: m/z 300 (M+H)⁺.

Step 7:Dimethyl-2-{[(amino-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioate

A solution ofbenzyl-(2S)-2-[amino(hydroxyimino)methyl]-4,4-difluoropyrrolidine-1-carboxylateand dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxedfor 1 hour under nitrogen and the solution was concentrated. Residue waspurified by flash chromatography on silica gel, (eluent: petroleumether:ethyl acetate=7.5:2.5), to give the desired product as a 3:1mixture of two isomers by ¹H NMR.

¹H NMR (DMSO-d₆, 300 MHz, 330 K) δ 7.45-7.25 (m, 5H), 6.63 (bs, 1.5H),6.30 (bs, 0.5H), 5.62 (s, 0.75H), 5.60 (s, 0.25H), 5.13 (s, 2H), 4.58(dd, J=9.1 and 4.9 Hz)+4.57 (dd, partially overlapped) (1H), 3.96-3.86(m, 2H), 3.79 (s, 2.2H), 3.74 (s, 0.8H), 3.66 (s, 0.8H), 3.61(s, 2.2H),2.93-2.81(m, 1H), 2.56-2.43 (partially under DMSO) (m, 1H).

MS: m/z 442 (M+H)⁺.

Step 8:Methyl-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-5,6-dihydroxypyrimidine-4-carboxylate

A solution ofdimethyl-2-{[(amino-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}methylidene)amino]oxy}but-2-enedioatein o-xylene was refluxed for 6 hours. Then the reaction was cooled downand concentrated at rotavapor. Ethyl ether was added until precipitationof a solid that was filtered, washed with other ethyl ether and dried togive the title pyrimidine as a brown solid. Two sets of signals, tworotamers (ratio 1:1) were present.

¹H NMR (DMSO-d₆, 400 MHz, 300 K) δ 12.97 (s, 1H), 10.38 (s, 1H),7.40-7.29 (m, 3H), 7.22-7.15 (m, 1H); 7.10-7.05 (m, 1H), 5.12 (d, J=12.6Hz, 0.5H) 5.10 (s, 1H), 4.89 (d, J=12.6 Hz, 0.5H), 4.86-4.72 (m, 1H),4.10-3.86 (m, 2H), 3.81 (s, 3H), 2.90-2.85 (m, 1H), 2.64-2.53 (partiallyunder DMSO) (m, 1H).

MS: m/z 410 (M+H)⁺.

Step 9: Methyl5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate

Methyl-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-5,6-dihydroxypyrimidine-4-carboxylatein dry pyridine was treated with benzoic anhydride (2 eq.) overnight atroom temperature.

The mixture was evaporated, taken up in ethyl acetate and washed withHCl 1N and brine. Organics were dried over Na₂SO₄, filtered andevaporated to obtain an oil which was purified by flash chromatographyon silica gel (eluent: ethyl acetate:petroleum ether=7:3).

¹H NMR (DMSO-d₆, 300 MHz, 330 K) δ 13.51 (bs, 1H), 8.10 (d, J=7.6 Hz,2H), 7.79 (t, J=7.1 Hz, 1H), 7.64 (t, J=7.6 Hz, 2H), 7.33-7.17 (m, 5H),5.13 (s, 2H), 4.99 (t, J=7.3 Hz, 1H), 4.09-3.97 (m, 2H), 3.77, (s, 3H),3.02-2.99 (m, 2H).

MS: m/z 514 (M+H)⁺.

Step 10:Methyl-5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Methyl5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylatedissolved in dry 1,4-dioxane was added to a suspension of LiH (1.4 eq.)in dioxane. The mixture was stirred at 38° C. for 45 minutes and thencooled down to room temperature. Dimethyl sulphate (1.3 eq.) was addedand the mixture was warmed to 58° C. for 1 hour. The reaction mixturewas cooled down to 16° C. and glacial acetic acid (0.1 eq) was added,followed by water and ethyl acetate. The combined organic layers weredried (Na₂SO₄), filtered and concentrated to an oil which waschromatographed through silica gel (eluent: ethyl acetate:petroleumether=3:7) to give the desired compound as a 1:1 mixture of two rotamersby ¹H NMR

¹H NMR (DMSO-d₆, 300 MHz, 300 K) δ 8.11-8.08 (m, 2H), 7.80 (t, J=7.7 Hz,1H), 7.67-7.65 (m, 2H), 7.36-7.10 (m, 5H), 5.50 (dd, J=9.2 and 4.7 Hz,1H), 5.22 (d, J=12.9 Hz, 0.5H), 5.14-4.95 (m, 1H), 4.93 (d, J=12.3 Hz,0.5H), 4.16-3.79 (m, 2H), 3.74 (s, 3H), 3.61 (s, 1.5H), 3.45 (s, 1.5H),3.25-3.11 (m, 1H), 2.89-2.74 (m, 1H). MS: m/z 528 (M+H)⁺.

Step 11:Benzyl-(2S)-4,4-difluoro-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate

Methyl-5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylatein dry MeOH was treated with 4-fluorobenzyl amine (2.5 eq.) at refluxfor 2 hours. Solvent was removed in vacuo and the residue was taken upin ethyl acetate, washed with HCl 1N, brine, dried over Na₂SO₄. Thefiltrate was concentrated in vacuo and triturated with ethyl ether toobtain the title compound as a 1.5:1 mixture of two rotamers by NMR.

¹H NMR (DMSO-d₆+TFA, 300 MHz, 300 K) δ 8.92 (bt, 0.4H), 8.69 (bt, 0.6H),7.36-7.31 (m, 4H), 7.20-7.09 (m, 4H), 6.97 (d, J=7.2 Hz, 1H), 5.34-5.25(m, 1H), 5.14 (d, J=12.4 Hz, 0.4H), 5.07-4.99 (m, 1.2H), 4.81 (d, J=12.2Hz, 0.4H), 4.51-4.48 (m, 2H), 4.38-4.21 (m, 1H), 4.07-3.96 (m, 1H), 3.59(s, 1.2H), 3.48 (s, 1.8H), 3.05-2.95 (m, 1H), 2.78-2.68 (m, 1H). MS: m/z517 (M+H)⁺.

Step 12:(2S)-4,4-difluoro-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidiniumtrifluoroacetate

A solution ofbenzyl-(2S)-4,4-difluoro-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylatein MeOH was treated with Pd/C 10% wt (10% w/w) for 3 hours at roomtemperature under H₂ atmosphere. The mixture was filtrated over a celitepad, concentrated in vacuo and treated with trifluoroacetic acid (10eq.). The acid in excess was removed in vacuo to obtain title product asa pale yellow solid after trituration with ethyl ether.

¹H NMR (DMSO-d₆+TFA, 300 MHz, 340K) δ 9.60 (bt, 1H), 7.39 (t, J=8 Hz,2H), 7.17 (t, J=8,8 Hz, 2H), 5.35 (t, J=8.4 Hz, 1H), 4.62 (dd, J=15.3and 6.6 Hz, 1H), 4.55 (dd, J=15.2 and 6.3 Hz, 1H), 4.05-3.87 (m, 2H),3.48 (s, 3H), 3.30-3.14 (m, 1H), 2.96-2.78 (m, 1H).

MS: m/z 383 (M+H)⁺.

Step 13:2-{(2S)-1-[(dimethylamino)(oxo)acetyl]-4,4-difluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

A solution of(2S)-4,4-difluoro-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidiniumtrifluoroacetate in chloroform and triethylamine (1.01 eq.) was treatedwith methyl chlorooxacetate (2 eq.) at 0° C. The mixture was allowed toreach room temperature for 2 hours. Dimethylamine (30 eq.) was added atroom temperature and the mixture left stirring over night. The mixturewas concentrated in vacuo and purified by preparative HPLC (Column: C₁₈,eluent:acetonitrile and water containing 0.1% trifluoroacetic acid). Toobtain the title product two rotamers (ratio 4:1) were found in ¹H NMR.

¹H NMR (DMSO-d₆+TFA, 300 MHz, 300 K) δ 9.23 (t, J=6.5 Hz, 0.8H), 9.10(bt, 0.2H), 7.34-7.31 (m, 2H), 7.11 (t, J=8.8 Hz, 2H), 5.48 (dd, J=8.9and 5.7 Hz, 1H), 4.53 (dd, J=15.0 and 6.7 Hz, 1H), 4.42 (dd, J=15.0 and6.2 Hz, 1H), 4.24-4.16 (m, 1H), 4.05-4.02 (t, J=11.8 Hz, 1H), 3.52 (s,2.4H), 3.45 (s, 0.6H), 3.15-3.04 (m, 1.6H), 2.84 (s, 2.4H), 2.80 (s,2.4H), 2.79-2.65 (m, 0.4H), 2.63 (s, 0.6H), 2.57 (s, 0.6H).

MS: m/z 482 (M+H)⁺.

EXAMPLE 212-[1,2-dimethyl-4-(methylsulfonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide

Step 1: 1-benzyl 4-tert-butyl2-cyano-2-methylpiperazine-1,4-dicarboxylate

To a cooled (−75° C.) solution of LDA 2M in heptane/THF (1.5 eq) in THF,a solution of1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (Bigge et al, Tetrahedron Lett. 1989, 30: 5193) in THF was addeddropwise at −75° C. After being stirred for 1 hour at −75° C., MeI (1.5eq) was added. After 2 hours at −75° C. the reaction mixture was leftwarming to r.t., evaporated, diluted with AcOEt, washed with NaHCO₃,water, brine and dried over Na₂SO₄. The crude was purified by flashchromatography on silica gel (petroleum ether/AcOEt, 85:15) to obtainthe title compound.

¹H NMR (DMSOd₆, 340K, 300 MHz) δ 7.45-7.30 (m, 5H), 5.19 (AA′ system,J=13 Hz, 2H), 4.05 (d, J=14 Hz, 1H), 3.87-3.78 (m, 1H), 3.66 (d, J=14Hz, 1H), 3.62-3.35 (m, 3H), 1.66 (s, 3H), 1.45 (s, 9H). MS: m/z 360(M+H)⁺.

Step 2: 1-benzyl 4-tert-butyl2-[(Z)-amino({[(1E)-3-methoxy-1-(methoxycarbonyl)-3-oxoprop-1-enyl]oxy}imino)methyl]-2-methylpiperazine-1,4-dicarboxylate.

A solution of 1-benzyl 4-tert-butyl2-cyano-2-methylpiperazine-1,4-dicarboxylate in EtOH was added to asolution of Et₃N (3.2 eq) and NH₂OH HCl (3 eq) in EtOH. The mixture wasstirred 2 hr at 40° C. After evaporation of the solvent, the residue wasdiluted with AcOEt, washed with water, dried over Na₂SO₄, filtered andconcentrated. The residue was further dissolved in chloroform anddimethylacetylenedicarboxylate (1.5 eq) added to the stirred solution.Reaction was refluxed over night. The mixture was evaporated and theresidue was purified by flash chromatography on silica gel (petroleumether/AcOEt, 65:35) affording the title compound as mixture of isomersin 3.5:1 ratio.

¹H NMR (DMSOd₆, 340K, 300 MHz). Two sets of signals were observed due tothe presence of the geometric isomers: δ 7.48-7.25 (m, 5H), 6.31(bs,1.56 H), 6.01 (bs, 0.44 H), 5.63 (s, 0.78 H), 5.55 (s, 0.22 H),5.12-5.02 (m, 2H), 3.85-3.60 (m, 9H), 3.60-3.45 (m, 2H), 3.45-3.31 (m,1H), 1.51 (s, 2.4H), 1.45 (s, 0.66 H), 1.41 (s, 9H).

MS: m/z 535 (M+H)⁺.

Step 3: 1-benzyl 4-tert-butyl2-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate

1-benzyl 4-tert-butyl2-[(Z)-amino({[(1E)-3-methoxy-1-(methoxycarbonyl)-3-oxoprop-1-enyl]oxy}imino)methyl]-2-methylpiperazine-1,4-dicarboxylatewas dissolved in xylene and stirred at 155° C. for 8 h. Afterevaporation of the solvent, the residue was dissolved in pyridine andbenzoic anhydride (1.5 eq) was added. The reaction mixture was stirredat room temperature over night, then pyridine was evaporated. Theresidue was diluted with AcOEt, the organic phase washed with HCl 1N,dried (Na₂SO₄) and evaporated. The title product was obtained by flashchromatography (eluent: petroleum ether/AcOEt 70/30).

¹H-NMR (DMSOd₆, 340K, 400 MHz) δ 12.96 (bs, 1H), 8.07 (d, J=7.2 Hz, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 2H), 7.37-7.22 (m, 5H),5.03 (s, 2H), 3.96 (dt, J₁=13.6 Hz, J₂=5.8 Hz, 1H), 3.80-3.52 (m, 7H),3.47-3.40 (m, 1H), 1.65 (s, 3H), .35 (s, 9H). MS: m/z 607 (M+H)⁺.

Step 4: 1-benzyl 4-tert-butyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate.

1-Benzyl 4-tert-butyl2-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylatewas added to a suspension of LiH (1.1 eq) in dioxane (7 ml/mmol) at roomtemperature. The mixture was stirred at 40° C. for 45 min, thendimethylsulfate (1.3 eq) was added and the temperature was raised to 60°C. After 1 h glacial acetic acid (0.1 eq) was added to the reactionmixture, followed by water (7 ml/mmol) and EtOAc (7 ml/mmol). Theaqueous layer was separated and extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄) and concentrated. The crude waspurified by flash chromatography on silica gel (AcOEt/petroleum ether,1:4) to separate the title compound A from B (ratio A/B 1.3/1).

A: ¹H NMR (CD₃CN, 320K, 300 MHz) δ 8.18 (d, J=7.2 Hz, 2H), 7.80 (t,J=7.5 Hz, 1H), 7.63 (t, J=7.8 Hz, 2H), 7.45-7.22 (m, 5H), 5.08 (AA′system, J=12 Hz, 2H), 4.18-3.88 (m, 3H), 3.81 (s, 3H), 3.68-3.46 (m, 5H,at 3.58 (s)), 3.40-3.22 (m, 1H), 1.75 (s, 3H), 1.49 (s, 9H).

MS: m/z 621 (M+H)⁺.

Step 5: Methyl5-(benzoyloxy)-2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate

1-Benzyl 4-tert-butyl2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylatewas dissolved in AcOEt (20 ml/mmol) and hydrogenated at atm pressure on10% (w/w) Pd/C over night. After filtration of the catalyst, solvent wasevaporated to give crude product.

¹H NMR (DMSOd6+TFA, 340K, 400 MHz) δ 8.08 (d, J=7.1 Hz, 2H), 7.787 (t,J=7.4 Hz, 1H), 7.63 (t, J=7.8 Hz, 2H), 4.30 (d, J=15.2 Hz, 1H),3.90-3.50 (m, 10H), 3.35-3.25 (m, 1H), 1.81(s, 3H), 1.37 (s, 9H).

MS (EI+) m/z 487 (M+H)⁺.

Step 6:2-[1,2-dimethyl-4-(methylsulfonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.

Crude methyl5-(benzoyloxy)-2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylatewas dissolved in MeOH, p-fluorobenzylamine (3.0 eq) was added and themixture was refluxed over night. Evaporation of the solvent affordedcrude product.

MS: m/z 476 (M+H)⁺.

Crude obtained in the previous step was dissolved in MeOH (20 ml/mmol)and NaCNBH₃ (2.8 eq), AcONa (3.2 eq) and HCHO 37% in H₂O (4 eq) wereadded. The reaction mixture was stirred at room temperature over night,evaporated and the crude solid (4-fluorobenzyl2-[4-(tert-butoxycarbonyl)-1,2-dimethylpiperazin-2-yl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate)obtained washed with Et₂O.

MS (EI+) m/z 490 (M+H)⁺.

Deprotection of Boc group was carried out in DCM/TFA (1:1, 10 ml/mmol)for 1 hour.

MS (EI+) m/z 390 (M+H)⁺. The crude product was dissolved in DCM, Et₃N(3.3 eq) and MeSO₂Cl (2.6 eq) were added and the reaction was stirred atroom temperature over night. The reaction mixture was evaporated and thecrude residue purified by preparative HPLC (C18, gradient ofCH₃CN/H₂O+0.01% TFA) to obtain the title product.

¹H NMR (CD₃CN+TFA, 320K, 400 MHz) δ 8.51 (bs, 1H), 7.46-7.36 (m, 2H),7.15-7.10 (m, 2H), 4.64 (d, J=6.4 Hz, 2H), 4.04 (dd, J₁=14.4 Hz, J₂=2.2Hz, 1H), 3.88-3.80 (m, 1H), 3.68 (dt, J₁=13.6 Hz, J₂=3.3 Hz, 1H), 3.61(s, 3H), 3.60-3.50 (m, 1H) 3.42-3.31(m, 2H), 2.94 (s, 3H), 2.81 (s, 3H),1.92 (s, 3H).

MS: m/z 468 (M+H)⁺.

Tables 1 and 2 below list compounds of the present invention which havebeen prepared. The tables provide the structure and name of eachcompound, the mass of its molecular ion plus 1 (M⁺) or molecular ionminus 1 (M⁻) as determined via FIA-MS, and the synthetic scheme employedto prepare the compound. When the compound was prepared as a salt, theidentity of the salt is included with the compound name. The syntheticscheme identified as “1*” in Table 1 is identical to Scheme 1 above,except for an additional deprotection step to remove Boc, Cbz, or benzylpresent in the 2-substituent in the pyrimidinone ring.

TABLE 1 Exp Structure Name M+ Scheme 1

N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide394 1 2

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide410 1 3

N-(2,3-dimethoxybenzyl)-2-{4-[(dimethylamino)methyl]phenyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 3 4

N-(4-fluorobenzyl)-2-{4-[(dimethylamino)methyl]phenyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 411 3 5

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 479 3 6

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(4-(pyrrolidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 437 3 7

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(piperidin-1-ylmethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 451 3 8

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 495 3 9

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 3 10

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 466 3 11

2-{4-[(diethylamino)methyl]phenyl}-N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 481 3 12

2{4-[(diethylamino)methyl]phenyl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 439 3 13

2-[(dimethylamino)(phenyl)methyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 411 3 14

N-(4-fluorobenzyl)-2-[(4-formylpiperazin-1-yl)(phenyl)methyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 480 3 15

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{phenyl[(pyridin-3-ylmethyl)amino]methyl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 474 3 16

2-benzyl-1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 425 1 17

1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-2-(2-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 425 1 18

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide368 1 19

2-benzyl-N-(2,3-dimethoxybenzyl)-1-[2-(dimethylamino)ethyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 467 1 20

2-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 480 3 21

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{4-[(2-pyridin-3-ylpiperidin-1-yl)methyl]phenyl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 528 3 22

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide276 (M−) 1 23

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide320 1 24

N-(4-fluoro-2-(trifluoromethyl)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(M−) 344 1 25

N-(3-chloro-4-methylbenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide308 1 26

5-hydroxy-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1-methyl-2-{4-((4-methylpiperazin-1-yl)methyl]phenyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 490 3 27

N-(4-fluorobenzyl)-5-hydroxy-2-(4-([(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 481 3 28

N-(4-fluorobenzyl)-5-hydroxy-2-(4-([(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl)phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 481 3 29

N-(4-fluorobenzyl)-2-(4-{[(4-fluorobenzyl)amino]methyl}-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 491 3 30

2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 467 1 31

1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 335 1 32

N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 355 1 33

2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-pyrrolidin-1-ylethyl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 451 1 34

2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-piperidin-1-ylethyl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 465 1 35

2-(1-benzylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 451 4 36

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 375 4 37

2-(1-benzylpiperidin-3-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 451 4 38

1-{3-[(dimethylamino)methyl]benzyl}-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 411 3 39

N-(2,3-dimethoxybenzyl)-1-[2-(dimethylamino)ethyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 377 1 40

N-(2,3-dimethoxybenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 397 1 41

N4-(4-fluorobenzyl)-5-hydroxy-1-methyl-N2-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxamide(TFA salt) 434 6 42

N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-[3-(pyrrolidin-1-ylmethyl)benzyl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 437 3 43

N-(4-fluorobenzyl)-5-hydroxy-1-[3-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 3 44

N-(4-fluorobenzyl)-5-hydroxy-1-{3-[(4-methylpiperazin-1-yl)methyl]benzyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 466 3 45

N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{3-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 529 3 46

N-(4-fluorobenzyl)-5-hydroxy-1-[2-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 3 47

N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 529 3 48

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-pyrrolidin-2-yl-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 347  1* 49

N4-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-N2-(pyridin-2-ylmethyl)-1,6-dihydropyrimidine-2,4-dicarboxamide(TFA salt) 412 6 50

N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 407 I 51

N-(4-fluorobenzyl)-5-hydroxy-1-[4-(morpholin-4-ylmethyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 3 52

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 390.9 7 53

2-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide366 1 54

2-(2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(HCl salt) 395  1* 55

2-[2-(4-benzoylpiperazin-1-yl)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide494 7 56

2-[1-(N,N-dimethylglycyl)piperidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 446 5 57

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-2,3-dihydro-1H-indol-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(HCL salt) 409 4 58

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(1,2,3,4-tetrahydroquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 409  1* 59

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 423 4 60

tert-butyl(2S,4R)-4-(benzyloxy)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate552.8 1 61

tert-butyl(2S,4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-hydroxypyrrolidine-1-carboxylate463.2  1* 62

2-[(2S,4R)-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453  1* 63

N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(HCl salt) 362.8  1* 64

N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 376.8 4 65

2-[(2S,4R)-4-(benzyloxy)-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 466.6 4 66

2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide557 5 67

2-[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 480 5 68

2-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide499 5 69

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 500 5 70

tert-butyl3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperazine-1-carboxylate(TFAsalt) 476 4 71

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 377 4 72

2-(1-ethyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 423 4 73

2-(1-benzoylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide465 5 74

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)piperidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 466 5 75

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 423 4 76

2-(1-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide451 5 77

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 452 5 78

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpyrrolidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 361 4 79

2-[(2S,4R)-4-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 558 5 80

2-[1-(dimethylamino)-2-phenylethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 425 4 81

2-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide467  1* 82

N-(4-fluorobenzyl)-5-hydroxy-2-(1-isobutyl-2,3-dihydro-1H-indol-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 451 4 83

N-(4-fluorobenzyl)-5-hydroxy-2-(1-isopropyl-2,3-dihydro-1H-indol-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 437 4 84

2-[1-(N,N-dimethylglycyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 432 5 85

2-{1-[(6-bromopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 531 5 86

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperazin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 376  1* 87

2-(1-benzoyl-4-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 480 4 88

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 514 5 89

2-(1-acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide389 5 90

2-[1-(cyclopropylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide415 5 91

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-(methylsulfonyl)pyrrolidin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide425 5 92

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-[(4-methylmorpholin-3-yl)carbonyl]pyrrolidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 474 5 93

2-(1,4-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxanude(TFA salt) 390 4 94

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-3-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 452 5 95

2-[(2S,4R)-1-acetyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide495 5 96

N-(4-fluorobenzyl-5-hydroxy-2-(1-isonicotinoylpyrrolidin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 452 5 97

2-{1-[(ethylamino)carbonyl]-pyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide418 5 98

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-methyl-1H-imidazol-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 455 5 99

2-[(2S,4R)-1-acetyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide405  1* 100

2-[1-(anilinocarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide466 5 101

2-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 404 4 102

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1-oxidopyridin-2-yl)carbonyl)pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide468 5 103

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide(TFA salt) 453 5 104

2-[(4R)-3-acetyl-1,3-thiazolidin-4-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide407 5

TABLE 2 Exp STRUCTURE Name M + 1 Scheme 1

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-methyl-4-(methylsulfonyl)piperazin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide454 5 2

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylthiomorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide393 4 3

N-[4-fluoro-2-(methylsulfonyl)benzyl]-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrialidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide531 1 4

2-(1-acetylpyrrolidin-2-yl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carbaxamide467 1 5

2-(3-acetyl-1,3-thiazolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide407 1 6

2-[1-(acetylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carbaxamide377 1 7

2-(1-acetylpyrrolidin-2-yl)-N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide415 1 8

2-(4-acetyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide418 5 9

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-methyl-4-(pyrazin-2-ylcarbonyl)piperizin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide482 5 10

2-(1-acetylpyrrolidin-2-yl)-5-hydroxy-1-methyl-N-[2-(methylthio)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide417 1 11

N-(4-fluorobenzyl)-5-hydroxy-2-[1-[(1H-imidazol-5-ylcarbonyl)amino]-1-methylethyl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide429 5 12

2-[1-benzoyl-4-(pyrazin-2-ylcarbonyl)piperazin-2-yl]-N-(4-fluorobenzyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide572 5 13

2-(4-benzoyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide480 5 14

2-[4-(benzyloxy)-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide559 5 15

2-(1-acetylpyrrolidin-2-yl)-N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide431 1 16

2-(1-acetylpyrrolidin-2-yl)-5-hydroxy-N-(2-methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide401 1 17

N-1-{1-(4-[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N-2-,N-2-dihydropyrimidine-4-carboxamide434 8 18

2-(1-acetylpyrrolidin-2-yl)-N-[2-(dimethylamino)benzyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide414 4 19

2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide389 1 20

N-(4-fluorobenzyl)-5-hydroxy-2-[4-hydroxy-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide469 5* 21

N-[1-(4-{[(4-fluorobenzyl)amino]carbonyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]imidazo[2,1-b][1,3]thiazole-6-carboxamide485 5 22

2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide407 1 23

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-4-[(1-methyl-1H-imidazol-2-yl)carbonyl]piperazin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide484 5 24

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide445 5 25

N-1-[1-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino]car-bonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-methylethyl}-N-2-,N-2-dimethylethanediamide512 8 26

2-(4-acetyl-1,2-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide432 5 27

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrimidin-4-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide453 1 28

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyrimidin-5-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide453 1 29

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-[(1H-pyrazol-5-ylcarbonyl)amino]ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide429 5 30

2-[(2R,4R)-1-acetyl-4-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide419 1 31

2-[1-[(dimethylamino)(oxo)acetyl]pyrroli-din-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide446 8 32

N-[1-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}car-bonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-methylethyl)imidazo[2,1-b][1,3]thiazole-6-carboxamide563 5 33

2-[(2R,4R)-1-benzoyl-4-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide481  5* 34

N-(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)-1-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide482 5 35

2-[1,2-dimethyl-4-(methylsulfonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide468 5 36

N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide391 4 37

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-[(methylsulfonyl)acetyl]pyrrolidin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide467 1 38

2-[(2S)-1-acetyl-4,4-difluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide425 1 39

2-[(2R,4R)-1-acetyl-4-ethoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide433 1 40

2-[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide397 4 41

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide495 1 42

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[morpholin-4-yl(oxo)acetyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide476 8 43

2-{(2R,4R)-1-[(dimethylamino)(oxo)acetyl]-4-methoxypyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide476 8 44

2-[(2S)-4,4-difluoro-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide489 5 45

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{(2S,4S)-1-methyl-4-[(methylsulfonyl)amino]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide454 4 46

2-[1-[(dimethylamino)sulfonyl]pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide454 5 47

2-{(2R,4R)-4-ethoxy-1-(methylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidinc-4-carboxamide476 8 48

2-[(2S)-4,4-difluoro-1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide489 5 49

2-[(2S)-4,4-difluoro-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide488 5 50

2-{(2S)-1-[(dimethylamino)(oxo)acetyl]-4,4-difluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide482 8 51

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[1-[morpholin-4-yl(oxo)acetyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide488 8 52

2-{(2S)-1-[(dimethylamino)(oxo)acetyl]pyrroli-din-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide446 8 52

2-{(2S)-1-[(dimethylamino)(oxo)acetyl]pyrroli-din-2-yl}-N-(4-fluoro-2-methoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide476 8 54

N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N1,N2,N2-trimethylethanediamide448 8 55

2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(4-fluoro-2-methoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide419 1 56

N-(4-fluorobenzyl)-2-[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide379 4 57

2-{(2S,4S)-1-[(dimethylamino)(oxo)acetyl]-4-fluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide464 8 58

N1-[1-(4-{[(3-chloro-4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide468 8

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein R¹ is (1) —H, (2)—C₁₋₆ alkyl, which is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —CN, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),—N(R^(a)R^(b)), —C(═O)—C₀₋₆ alkyl-N(R^(a)R^(b)), N(R^(a))—C(═O)—C₀₋₆alkyl-N(R^(b)R^(c)), —SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),—N(R^(a))—C(═O)R^(b),

 or —N(R^(a))C(═O)C(═O)N(R^(a)R^(b)), (3) —R^(k), (4) —C₁₋₆ alkyl-R^(k),wherein: (i) the alkyl is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —CN, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),—N(R^(a))C(═O)—C₀₋₆ alkyl-N(R^(b)R^(c)), or —N(R^(a))—C₂₋₆ alkyl-OH withthe proviso that the —OH is not attached to the carbon alpha toN(R^(a)); and (ii) the alkyl is optionally mono-substituted with —R^(s),—C₁₋₆ alkyl-R^(s), —N(R^(a))—C(═O)—C₀₋₆ alkyl-R^(s), —N(R^(a))—C₀₋₆alkyl-R^(s), —O—C₀₋₆ alkyl-R^(s), or —N(R^(a))—C(═O)—C₀₋₆ alkyl-R^(s);wherein R^(s) is (a) aryl which is optionally substituted with one ormore substituents each of which is independently halogen, —OH, —C₁₋₆alkyl, —C₁₋₆ alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, methylenedioxy attached to two adjacent carbon atoms, oraryl; (b) a 4- to 8-membered saturated heterocyclic ring containing from1 to 4 heteroatoms independently selected from N, O and S; wherein thesaturated heterocyclic ring is optionally substituted with one or moresubstituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —C(═O)—C₀₋₆ alkyl-N(R^(a)R^(b)), —SO₂R^(a), oxo,aryl, or —C₁₋₆ alkyl-aryl; or (c) a 5- to 7-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; wherein the heteroaromatic ring is optionally substituted with one ormore substituents each of which is independently halogen, —C₁₋₆ alkyl,—C₁₋₆ alkyl-OR^(a), —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,oxo, or aryl; (5) —C₀₋₆ alkyl-O—C₀₋₆ alkyl-R^(k), (6) —C₀₋₆alkyl-S(O)_(n)—C₀₋₆ alkyl-R^(k), (7) —O—C₁₋₆ alkyl-OR^(k), (8) —O—C₁₋₆alkyl-O—C₁₋₆ alkyl-R^(k), (9) —O—C₁₋₆ alkyl-S(O)_(n)R^(k), (10) —C₀₋₆alkyl-N(R^(a))—R^(k), (11) —C₀₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-R^(k), (12)—C₀₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-OR^(k), (13) —C₀₋₆ alkyl-C(═O)—R^(k),(14) —C₀₋₆ alkyl-C(═O)N(R^(a))—C₀₋₆ alkyl-R^(k), (15) —C₀₋₆alkyl-N(R^(a))C(═O)—C₀₋₆ alkyl-R^(k), (16) —C₀₋₆alkyl-N(R^(a))C(═O)—O—C₀₋₆ alkyl-R^(k), or (17) —C₀₋₆alkyl-N(R^(a))C(═O)C(═O)R^(k); R² is —C₁₋₆ alkyl which is optionallysubstituted with one or more substituents each of which is independently(1) halogen, (2) —OH, (3) —CN, (4) —O—C₁₋₆ alkyl, (5) —O—C₁₋₆ haloalkyl,(6) —C(═O)R^(a), (7) —CO₂R^(a), (8) —SR^(a), (9) —S(═O)R^(a), (10)—N(R^(a)R^(b)), (11) —C(═O)N(R^(a)R^(b)), (12) —N(R^(a))—C(═O)—C₁₋₆alkyl-N(R^(b)R^(c)), (13) —SO₂R^(a), (14) —N(R^(a))SO₂R^(b), (15)—SO₂N(R^(a)R^(b)), (16) —N(R^(a))—C(R^(b))═O, (17) —C₃₋₈ cycloalkyl,(18) aryl, wherein the aryl is optionally substituted with one or moresubstituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C₀₋₆ alkyl-N(R^(a)R^(b)),or —C₁₋₆ alkyl substituted with a 5- or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₆ alkyl, oxo, or a 5- or 6-membered heteroaromaticring containing from 1 to 4 heteroatoms independently selected from N, Oand S; or (19) a 5- to 8-membered monocyclic heterocycle which issaturated or unsaturated and contains from 1 to 4 heteroatomsindependently selected from N, O and S; wherein the heterocycle isoptionally substituted with one or more substituents each of which isindependently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, oxo, phenyl, or naphthyl; withthe proviso that none of the following substituents is attached to thecarbon atom in the —C₁₋₆ alkyl group that is attached to the ringnitrogen: halogen, —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —SR^(a),—S(═O)R^(a), or —N(R^(a))—C(R^(b))═O; R³ is —H or —C₁₋₆ alkyl; R⁴ is (1)H, (2) C₁₋₆ alkyl which is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),—SR^(a), —S(═O)R^(a), —SO₂R^(a), or —N(R^(a))CO₂R^(b), (3) C₁₋₆ alkylwhich is optionally substituted with one or more substituents each ofwhich is independently halogen, —OH, or O—C₁₋₄ alkyl, and which issubstituted with 1 or 2 substituents each of which is independently: (i)C₃₋₈ cycloalkyl, (ii) aryl, (iii) a fused bicyclic carbocycle consistingof a benzene ring fused to a C₅₋₇ cycloalkyl, (iv) a 5- or 6-memberedsaturated heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, (v) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, or (vi) a 9- or 10-membered fused bicyclicheterocycle containing from 1 to 4 heteroatoms independently selectedfrom N, O and S, wherein at least one of the rings is aromatic, (4) C₂₋₅alkynyl optionally substituted with aryl, (5) C₃₋₈ cycloalkyl optionallysubstituted with aryl, (6) aryl, (7) a fused bicyclic carbocycleconsisting of a benzene ring fused to a C₅₋₇ cycloalkyl, (8) a 5- or6-membered saturated heterocyclic ring containing from 1 to 4heteroatoms independently selected from N, O and S, (9) a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, or (10) a 9- or 10-memberedfused bicyclic heterocycle containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein at least one of therings is aromatic; wherein each aryl in (3)(ii) or the aryl in (4), (5)or (6) or each fused carbocycle in (3)(iii) or the fused carbocycle in(7) is optionally substituted with one or more substituents each ofwhich is independently halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-OR^(a),—C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,—N(R^(a)R^(b)), —C₁₋₆ alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)),—C(═O)R^(a), —CO₂R^(a), —C₁₋₆ alkyl-CO₂R^(a), —OCO₂R^(a), —SR^(a),—S(═O)R^(a), —SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),—N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₆ alkyl-N(R^(a))CO₂R^(b),aryl, —C₁₋₆ alkyl-aryl, —O-aryl, or —C₀₋₆ alkyl-het wherein het is a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, and het is optionally fused witha benzene ring, and is optionally substituted with one or moresubstituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a); eachsaturated heterocyclic ring in (3)(iv) or the saturated heterocyclicring in (8) is optionally substituted with one or more substituents eachof which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, oxo, aryl, or a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; and each heteroaromatic ring in (3)(v) or theheteroaromatic ring in (9) or each fused bicyclic heterocycle in (3)(vi)or the fused bicyclic heterocycle in (10) is optionally substituted withone or more substituents each of which is independently halogen, —C₁₋₆alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, aryl, or—C₁₋₆ alkyl-aryl; or alternatively R³ and R⁴ together with the N towhich both are attached form a C₃₋₇ azacycloalkyl which is optionallysubstituted with one or more substituents each of which is independently—C₁₋₆ alkyl or oxo; each R^(a), R^(b), R^(c), and R^(d) is independently—H or —C₁₋₆ alkyl; R^(k) is carbocycle or heterocycle, wherein thecarbocycle or heterocycle is optionally substituted with one or moresubstituents each of which is independently (1) halogen, (2) —OH, (3)—CN, (4) —C₁₋₆ alkyl, which is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —CN, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),—N(R^(a)R^(b)), —C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)),N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), —SO₂R^(a), —N(R^(a))SO₂R^(b),—SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O, (5) —O—C₁₋₆ alkyl, which isoptionally substituted with one or more substituents each of which isindependently halogen, —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),—C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)), N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)),—SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or—N(R^(a))—C(R^(b))═O, (6) —NO₂, (7) oxo, (8) —C(═O)R^(a), (9) —CO₂R^(a),(10) —SR^(a), (11) —S(═O)R^(a), (12) —N(R^(a)R^(b)), (13)—C(═O)N(R^(a)R^(b)), (14) —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)), (15)—N(R^(a))C(═O)R^(b), (16) —SO₂R^(a), (17) —SO₂N(R^(a)R^(b)), (18)—N(R^(a))SO₂R^(b), (19) —R^(m), (20) —C₁₋₆ alkyl-R^(m), wherein thealkyl is optionally substituted with one or more substituents each ofwhich is independently halogen, —OH, —CN, —C₁₋₆ haloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a),—N(R^(a)R^(b)), —N(R^(a))CO₂R^(b), —SO₂R^(a), —N(R^(a))SO₂R^(b),—SO₂N(R^(a)R^(b)), or —N(R^(a))—C(R^(b))═O, (21) —C₀₋₆alkyl-N(R^(a))—C₀₋₆ alkyl-R^(m), (22) —C₀₋₆ alkyl-O—C₀₋₆ alkyl-R^(m),(23) —C₀₋₆ alkyl-S—C₀₋₆ alkyl-R^(m), (24) —C₀₋₆ alkyl-C(═O)—C₀₋₆alkyl-R^(m), (25) —C(═O)—O—C₀₋₆ alkyl-R^(m), (26) —C(═O)N(R^(a))—C₀₋₆alkyl-R^(m), (27) —N(R^(a))C(═O)—R^(m), (28) —N(R^(a))C(═O)—C₁₋₆alkyl-R^(m), wherein the alkyl is optionally substituted with one ormore substituents each of which is independently halogen, —OH, —CN,—C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),—SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or—N(R^(a))—C(R^(b))═O, (29) —N(R^(a))—C(═O)—N(R^(b))—C₀₋₆ alkyl-R^(m),(30) —N(R^(a))—C(═O)—O—C₀₋₆ alkyl-R^(m), (31)—N(R^(a))—C(═O)—N(R^(b))—SO₂—C₀₋₆ alkyl-R^(m), (32)—C(═O)—C(═O)—N(R^(a)R^(b)), (33) —C(═O)—C₁₋₆ alkyl-SO₂R^(a), or (34)—C(═O)—C(═O)R^(m); carbocycle in R^(k) is (i) a C₃ to C₈ monocyclic,saturated or unsaturated ring, (ii) a C₇ to C₁₂ bicyclic ring system or(iii) a C₁₁ to C₁₆ tricyclic ring system, wherein each ring in (ii) or(iii) is independent of or fused to the other ring or rings and eachring is saturated or unsaturated; heterocycle in R^(k) is (i) a 4- to8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to12-membered bicyclic ring system, or (iii) an 11 to 16-memberedtricyclic ring system; wherein each ring in (ii) or (iii) is independentof or fused to the other ring or rings and each ring is saturated orunsaturated; the monocyclic ring, bicyclic ring system, or tricyclicring system contains from 1 to 6 heteroatoms selected from N, O and Sand a balance of carbon atoms; and wherein any one or more of thenitrogen and sulfur heteroatoms is optionally be oxidized, and any oneor more of the nitrogen heteroatoms is optionally quaternized; eachR^(m) is independently C₃₋₈ cycloalkyl; aryl; a 5- to 8-memberedmonocyclic heterocycle which is saturated or unsaturated and containsfrom 1 to 4 heteroatoms independently selected from N, O and S; or a 9-to 10-membered bicyclic heterocycle which is saturated or unsaturatedand contains from 1 to 4 heteroatoms independently selected from N, Oand S; wherein any one or more of the nitrogen and sulfur heteroatoms inthe heterocycle or bicyclic heterocycle is optionally oxidized and anyone or more of the nitrogen heteroatoms is optionally quaternized; andwherein the cycloalkyl or the aryl defined in R^(m) is optionallysubstituted with one or more substituents each of which is independentlyhalogen, —C₁₋₆ alkyl optionally substituted with —O—C₁₋₄ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —N(R^(a)R^(b)), aryl, or—C₁₋₆ alkyl-aryl; and the monocyclic or bicyclic heterocycle defined inR^(m) is optionally substituted with one or more substituents each ofwhich is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, oxo, aryl, —C₁₋₆ alkyl-aryl, —C(═O)-aryl,—CO₂-aryl, —CO₂—C₁₋₆ alkyl-aryl, a 5- or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, or a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and each n is independently an integer equal to zero, 1 or
 2. 2. Themethod according to claim 1, wherein in the compound of Formula I or apharmaceutically acceptable salt thereof: R¹ is: (1) —H, (2) —C₁₋₄alkyl, which is optionally substituted with from 1 to 4 substituentseach of which is independently halogen, —OH, —CN, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, —C(═O)R^(a), —CO₂R^(a), —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),—C(═O)—C₀₋₄ alkyl-N(R^(a)R^(b)), N(R^(a))—C(═O)—C₀₋₄alkyl-N(R^(b)R^(c)), —SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),—N(R^(a))—C(═O)R^(b),

 —N(R²)C(═O)C(═O)N(R^(a)R^(b)), (3) —R^(k), (4) —C₁₋₄ alkyl-R^(k),wherein: (i) the alkyl is optionally substituted with from 1 to 4substituents each of which is independently halogen, —OH, —CN, —O—C₁₋₄alkyl, —O—C₁₋₄ haloalkyl, —N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),—N(R^(a))C(═O)—C₀₋₄ alkyl-N(R^(b)R^(c)), or —N(R^(a))—(CH₂)₂₋₄—OH; and(ii) the alkyl is optionally mono-substituted with —R^(s),—N(R^(a))—C(═O)—C₀₋₄ alkyl-R^(s), —N(R^(a))—C₀₋₄ alkyl-R^(s), —O—C₀₋₄alkyl-R^(s), or —N(R^(a))—C(═O)—C₀₋₄ alkyl-R^(s); wherein R^(s) is (a)aryl which is optionally substituted with from 1 to 3 substituents eachof which is independently halogen, —OH, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a),—C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, methylenedioxyattached to two adjacent carbon atoms, or phenyl; (b) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the heteroaromatic ring is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄ haloalkyl, oxo, or phenyl; or (c) a 5- or 6-memberedsaturated heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S; wherein the saturatedheterocyclic ring is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —C(═O)—C₀₋₄ alkyl-N(R^(a)R^(b)), —SO₂R^(a), oxo,or phenyl, (5) —(CH₂)₀₋₃—C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k), (6) —C(C₁₋₄alkyl)₂N(R^(a))C(═O)R^(b), (7) —C(C₁₋₄ alkyl)₂N(R^(a))C(═O)R^(k), or (8)—C(C₁₋₄ alkyl)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c)).
 3. The method accordingto claim 2, wherein in the compound of Formula I or a pharmaceuticallyacceptable salt thereof: R² is methyl R³ is —H; and R⁴ is —CH₂-phenyl,wherein the phenyl is optionally substituted with from 1 to 3substituents, each of which is independently —F, —Br, —Cl, —OH, —C₁₋₄alkyl, —C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl, —SO₂—C₁₋₄ alkyl, —S—C₁₋₄ alkyl,—N(CH₃)₂, or —O—C₁₋₄ fluoroalkyl.
 4. The method according to claim 3,wherein in the compound of Formula I or a pharmaceutically acceptablesalt thereof: R^(k) is phenyl; a 5- or 6-membered saturated heterocyclicring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1O atoms, and 0 or 1 S atoms; a 5- or 6-membered heteroaromatic ringcontaining 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1 Oatoms, and 0 or 1 S atoms; or a bicyclic heterocycle which is a benzenering fused to a 5- or 6-membered saturated heterocyclic ring containing1 or 2 nitrogen atoms; wherein: (a) the phenyl, the saturatedheterocyclic ring, heteroaromatic ring, or bicyclic heterocycle isoptionally substituted with from 1 to 3 substituents each of which isindependently (1) fluoro, (2) chloro, (3) bromo, (4) —OH (5) —CF₃, (6)—C₁₋₄ alkyl, which is optionally substituted with 1 or 2 substituentseach of which is independently —OH, —CN, —O—C₁₋₄ alkyl, —OCF₃,—N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), orN(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)), (7) —OCF₃, (8) —O—C₁₋₄ alkyl (9)—C(═O)R^(a), (10) —CO₂R^(a), (11) —SR^(a), (12) —SR^(a), (13)—N(R^(a)R^(b)), (14) —C(═O)N(R^(a)R^(b)), (15)—C(═O)—(CH₂)₁₋₂—N(R^(a)R^(b)), (16) —N(R^(a))C(═O)R^(b), or (17)—SO₂R^(a); (b) the phenyl is optionally mono-substituted with (1)—(CH₂)₁₋₂—R^(m), or (2) —(CH₂)₀₋₂—N(R^(a))—(CH₂)₀₋₂—R^(m); and (c) thesaturated heterocyclic ring, heteroaromatic ring, or bicyclicheterocycle is optionally mono- or di-substituted with (1) oxo (2)—(CH₂)₁₋₂—R^(m), (3) —O—(CH₂)₁₋₂—R^(m), or (4)—(CH₂)₀₋₁—C(═O)—(CH₂)₀₋₂—R^(m); and each R^(m) is independentlycyclopropyl; phenyl; a 5- or 6-membered saturated heterocyclic ringselected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, and morpholinyl; or a 5- or 6-membered heteroaromatic ringselected from thienyl, pyridyl optionally in the form of an N-oxide,imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isooxazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl,triazolyl, tetrazolyl, furanyl, and pyridazinyl; wherein the cyclopropylis unsubstituted; the phenyl is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, —CF₃,—O—C₁₋₄ alkyl, —OCF₃, or —N(R^(a)R^(b)); the saturated heterocyclic ringis optionally substituted with 1 or 2 substituents each of which isindependently —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, oxo, phenyl,—(CH₂)₁₋₂-phenyl, —C(═O)-phenyl, —CO₂-phenyl, or —CO₂—CH₂-phenyl; andthe heteroaromatic ring is optionally substituted with 1 or 2substituents each of which is independently —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄alkyl, —OCF₃, oxo, phenyl, or —(CH₂)₁₋₂-phenyl.
 5. The method accordingto claim 4, wherein in the compound of Formula I or a pharmaceuticallyacceptable salt thereof: R¹ is: (1) —H, (2) —C₁₋₄ alkyl, which isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —N(R^(a)R^(b)), or —C(═O)—(CH₂)₀₋₂—N(R^(a)R^(b)), (3) —R^(k),(4) —(CH₂)₁₋₄—R^(k), wherein: (i) the —(CH₂)₁₋₄— moiety is optionallysubstituted with 1 or 2 substituents each of which is independentlyhalogen, —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —N(R^(a)R^(b)); and(ii) the —(CH₂)₁₋₄— moiety is optionally mono-substituted with —R^(s) or—N(R^(a))—(CH₂)₁₋₂—R^(s); wherein R^(s) is (a) phenyl which isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl; or (b) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the heteroaromatic ring is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄alkyl, or —O—C₁₋₄ haloalkyl; or (c) a 5- or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), or —CO₂R^(a), (5)—C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k), (6) —C(CH₃)₂N(R^(a))C(═O)R^(b), (7)—C(CH₃)₂N(R^(a))C(═O)R^(k), or (8)—C(CH₃)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c)).
 6. The method according toclaim 1, wherein the compound of Formula I is a compound selected fromthe group consisting of:N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide;N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;and pharmaceutically acceptable salts thereof.
 7. The method accordingto claim 6, wherein the compound of Formula I isN1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamideor a pharmaceutically acceptable salt thereof.
 8. The method accordingto claim 6, wherein the compound of Formula I isN-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamideor a pharmaceutically acceptable salt thereof.
 9. The method accordingto claim 1, which is a method of inhibiting HIV-1 integrase.
 10. Themethod according to claim 9, wherein the compound of Formula I is acompound selected from the group consisting of:N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide;N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;and pharmaceutically acceptable salts thereof.
 11. The method accordingto claim 10, wherein the compound of Formula I isN1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamideor a Pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 10, wherein the compound of Formula I isN-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamideor a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 3, wherein in the compound of Formula I or a pharmaceuticallyacceptable salt thereof: R^(k) is C₃₋₈ cycloalkyl; aryl selected fromphenyl and naphthyl; a bicyclic carbocycle selected from indanyl andtetrahydronaphthyl; a 5- or 6-membered saturated heterocyclic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S; or a bicyclicheterocycle which is a benzene ring fused to a 5- or 6-memberedsaturated or unsaturated heterocyclic ring containing from 1 to 3heteroatoms independently selected from N, O and S; wherein thecycloalkyl, aryl, bicyclic carbocycle, saturated heterocyclic ring,heteroaromatic ring, or bicyclic heterocycle is optionally substitutedwith from 1 to 4 substituents each of which is independently (1)halogen, (2) —OH, (3) —CN, (4) —C₁₋₄ haloalkyl, (5) —C₁₋₄ alkyl, whichis optionally substituted with from 1 to 3 substituents each of which isindependently —OH, —CN, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),—C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)), N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)),—SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or—N(R^(a))—C(R^(b))═O, (6) —O—C₁₋₄ haloalkyl (7) —O—C₁₋₄ alkyl, which isoptionally substituted with from 1 to 3 substituents each of which isindependently —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —SR^(a), —S(═O)R^(a), —N(R^(a)R^(b)),—C(═O)—(CH₂)₀₋₂N(R^(a)R^(b)), N(R^(a))—C(═O)—(CH₂)₀₋₂N(R^(b)R^(c)),—SO₂R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), or—N(R^(a))—C(R^(b))═O, (8) —NO₂, (9) oxo, (10) —C(═O)R^(a), (12) —SR^(a),(13) —S(═O)R^(a), (14) —N(R^(a)R^(b)), (15) —C(═O)N(R^(a)R^(b)), (16)—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)), (17) —N(R^(a))C(═O)R^(b), (18)—SO₂R^(a), (18) —SO₂N(R^(a)R^(b)), (19) —N(R^(a))SO₂R^(b), (20) —R^(m),(21) —C₁₋₄ alkyl-R^(m), (22) —(CH₂)₀₋₂—N(R^(a))—(CH₂)₀₋₂—R^(m), (23)—(CH₂)₀₋₂—O—(CH₂)₀₋₂—R^(m), (24) —(CH₂)₀₋₂—S—(CH₂)₀₋₂—R^(m), (25)—(CH₂)₀₋₂—C(═O)—(CH₂)₀₋₂—R^(m), (26) —C(═O)—O—(CH₂)₀₋₂—R^(m), (27)—C(═O)N(R^(a))—R^(m), or (28) —C(═O)—C(═O)N(R^(a)R^(b)); and each R^(m)is independently C₃₋₇ cycloalkyl; aryl selected from phenyl andnaphthyl; a 5- or 6-membered saturated heterocyclic ring containing from1 to 4 heteroatoms independently selected from N, O and S; a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein any N is optionallyoxidized to form an N-oxide; or a bicyclic heterocycle which is abenzene ring fused to a 5- or 6-membered, saturated or unsaturatedheterocyclic ring containing from 1 to 3 heteroatoms selected from N, Oand S; wherein: the cycloalkyl or the aryl defined in R^(m) isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—₁₋₄ alkyl,—O—C₁₋₄ haloalkyl, —N(R^(a)R^(b)), phenyl, or —(CH₂)₁₋₂-phenyl; thesaturated heterocyclic ring defined in R^(m) is optionally substitutedwith from 1 to 4 substituents each of which is independently —C₁₋₄ alkyloptionally substituted with —O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄ haloalkyl, oxo, phenyl, —(CH₂)₁₋₂-phenyl, —C(═O)-phenyl,—CO₂-phenyl, —CO₂—(CH₂)₁₋₂-phenyl, a 5- or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, or a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and the heteroaromatic ring or the bicyclic heterocycle defined inR^(m) is optionally substituted with from 1 to 4 substituents each ofwhich is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄ haloalkyl, oxo, phenyl, or —(CH₂)₁₋₂-phenyl; or apharmaceutically acceptable salt thereof.
 14. The method according toclaim 13, wherein in the compound of Formula I or a pharmaceuticallyacceptable salt thereof: R¹ is: (1) —H, (2) —C₁₋₄ alkyl, which isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —N(R^(a)R^(b)), or —C(═O)—(CH₂)₀₋₂—N(R^(a)R^(b)), (3) —R^(k),(4) —(CH₂)₁₋₄—R^(k), wherein: (i) the —(CH₂)₁₋₄— moiety is optionallysubstituted with 1 or 2 substituents each of which is independentlyhalogen, —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or —N(R^(a)R^(b)); and(ii) the —(CH₂)₁₋₄— moiety is optionally mono-substituted with —R^(s) or—N(R^(a))—(CH₂)₁₋₂—R^(s); wherein R^(s) is (a) phenyl which isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl; or (b) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the heteroaromatic ring is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl, —O—C₁₋₄alkyl, or —O—C₁₋₄ haloalkyl; or (c) a 5- or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, —C₁₋₄ alkyl-OR^(a), —C₁₋₄ haloalkyl,—O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —C(═O)R^(a), or —CO₂R^(a), (5)—C(═O)N(R^(a))—(CH₂)₀₋₃—R^(k), (6) —C(CH₃)₂N(R^(a))C(═O)R^(b), (7)—C(CH₃)₂N(R^(a))C(═O)R^(k), or (8)—C(CH₃)₂N(R^(a))C(═O)C(═O)N(R^(b)R^(c)).